https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=R.+Jeremy+JohnsonProteopedia - User contributions [en]2026-09-24T09:19:59ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Insulin_receptor&diff=4386079Insulin receptor2025-10-23T19:32:50Z<p>R. Jeremy Johnson: </p>
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<div>{{BAMBED<br />
|DATE=December 3, 2020<br />
|OLDID=3326280<br />
|BAMBEDDOI=10.1002/bmb.21560<br />
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==Insulin Receptor==<br />
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulins Bound: (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=6SOF 6SOF]). Alpha subunits in blue, beta subunits in orange, and 4 insulin molecules bound in green.' scene='83/839263/Intro_scene/2'><br />
<br />
==Function of the Receptor==<br />
The insulin receptor is a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] receptor that resides in the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] and is activated by the binding of insulin.<ref name="Meyts"/> The insulin receptor belongs to the large class of [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase] (RTKs). [[Receptor tyrosine kinases|RTKs]] are found at the cell surface and have a high affinity for a particular ligand. RTKs are made up of three distinct parts: an extracellular domain with ligand binding sites, a transmembrane region, and an intracellular domain with the tyrosine kinases that initiate intracellular signaling cascades.<ref name="Meyts"/><br />
<br />
The insulin receptor binds the [[insulin]] hormone and initiates a cascade of events within the cell. The receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin targeted cells. These cells are found in various organs, such as the liver, and tissues, including skeletal muscle and adipose.<ref name="Boucher"> PMID: 24384568</ref> The insulin receptor is activated by multiple insulin molecules binding to various sites on the receptor.<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref> Once activated, the receptor serves as the gateway for the regulation of various cellular processes including glucose transport, glycogen storage, [http://en.wikipedia.org/wiki/Autophagy autophagy], [http://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, problems with the insulin receptor are associated with the development of diseases such as Alzheimer's, type II diabetes, and cancer.<ref name="Scapin"> DOI:10.1038/nature26153</ref> <br />
<br />
Through recent [http://en.wikipedia.org/wiki/Transmission_electron_cryomicroscopy cryo-EM] structures of the insulin receptor bound in various conformations, a complete three-dimensional understanding of the conformational changes in the insulin receptor upon insulin binding are finally coming into focus. Evaluation of the structural composition and the biochemical properties of the insulin receptor reveals details about the role of the receptor in crucial cellular processes.<br />
<br />
See also [[Kinase-linked, enzyme-linked and related receptors]], [[Insulin signal transduction pathway]]<br><br />
<br />
<br />
==Insulin==<br />
<scene name='83/839263/Insulin_molecule/3'>Insulin</scene> is a [http://en.wikipedia.org/wiki/Hormone hormone] made of two separate amino acid chains that are bound by multiple disulfide bonds. Insulin is synthesized and secreted from the [http://en.wikipedia.org/wiki/Pancreatic_islets islets of Langerhans] of the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, insulin moves through the bloodstream and binds to unactivated insulin receptors residing in the plasma membrane. Binding of insulin to the insulin receptor is a complex process, which involves negative cooperativity among insulin molecules.<ref name="Meyts"> DOI:10.1007/BF00400837</ref> <ref name="Uchikawa" /> <ref name="Schäffer"> PMID: 1472036</ref> Current hypotheses propose that the receptor is fully activated only after multiple insulin molecules are bound.<ref name="Uchikawa" /> The binding of the increased amount of insulin to the insulin receptors will activate their downstream pathways to initiate glucose uptake by the phosphorylation of the [http://en.wikipedia.org/wiki/Insulin_receptor_substrate Insulin Receptor Substrate] (IRS).<ref name= "White"> PMID: 8276779</ref> The transport of extracellular glucose into the cell allows this glucose to be converted to [http://en.wikipedia.org/wiki/Glycogen glycogen] for storage and later usage.<br />
<br />
==Insulin Receptor Structural Overview==<br />
The insulin receptor is a [http://en.wikipedia.org/wiki/Dimer_(chemistry) dimer] of <scene name='83/839263/Alpha_and_beta_subunit/3'>heterodimers</scene> made of two <scene name='83/832953/Alpha_subunits/5'>alpha subunits</scene> and two <scene name='83/832953/Beta_subunits/4'>beta subunits</scene>. <ref name="Tatulian">PMID:26322622</ref> Within the extracellular ectodomain, there are four potential <scene name='83/832953/Binding_sites/3'>binding sites</scene> that can interact with insulin ligands on the extracellular side of the membrane. The full extracellular and intracellular components of the insulin receptor have only been imaged in separate sections but a larger picture of how these sections combine to initiate downstream tyrosine [http://en.wikipedia.org/wiki/Autophosphorylation autophosphorylation] is emerging.<ref name= "Hubbard"> DOI: 10.1093/emboj/16.18.5572 </ref><br />
<br />
===Alpha Subunits===<br />
[[Image:Harrison Image2.png|thumb|right|300px|Figure 1: Insulin receptor apo receptor. Site L1' is colored a dark green, CR' is orange, L2' is bright blue, L2 is yellow, CR is red, L1 is dark blue, FnIII-1 is brown, and FnIII-2 is light pink. Insulin is shown bound and is colored dark pink. [http://www.rcsb.org/structure/6CE7 PDB 6CE7]]]<br />
The <scene name='83/832953/Alpha_subunits/5'>alpha subunits</scene> make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a <scene name='83/832953/Alpha_c_helix/6'>an α-chain C-terminal helix (α-CT)</scene> (Figure 1).<ref name="Scapin"> PMID 29512653 </ref> α-CT has a unique position that allows it to reach across the receptor and interact with the insulin at the binding site on the opposing side of the receptor. The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/2'>cysteine residues</scene> on each alpha subunit. The disulfide bonds are important to the overall stabilization of the molecule as it binds to insulin. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/17'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/13'>sites 2 and 2'</scene> (Figure 2). The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity for insulin binding than sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly.<ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> <br />
[[Image:4 sites highlighted - Harrison.png|thumb|right|300px|Figure 2: The four binding sites of insulin. Sites 1 and 1' are colored green, sites 2 and 2' are colored red. [http://www.rcsb.org/structure/6SOF PDB 6SOF]]]<br />
<br />
===Beta Subunits===<br />
The <scene name='83/832953/Beta_subunits/4'>beta subunits</scene> spans from the extracellular domain across the transmembrane region and into the intracellular portion of the insulin receptor. The beta subunit is composed of part of [http://en.wikipedia.org/wiki/Fibronectin fibronectin] domain III-2 and all of Fibronectin domain III-3.<ref name="Scapin" /> The beta subunit's FnIII-3 domain has links through the transmembrane region into the intracellular part of the membrane. Cryo-EM provided clear representations of the FnIII-2 and FnIII-3 domains (Figure 1) but are missing the transmembrane and intracellular regions. Although the FnIII-3 domain is connected to the transmembrane and intracellular regions, the active <scene name='83/839263/T-shape/4'>T-shape</scene> conformation (Figure 3) likely extends all the way to the tyrosine kinase domain region (see [http://www.rcsb.org/structure/4XLV PDB 4XLV]).<ref name= "Cabail"> DOI: 10.1038/ncomms7406 </ref> <br />
<br />
===Subunit Organization===<br />
The alpha and beta subunits of the extracellular domains fold over one another and form a <scene name='83/839263/V_shape/3'>V-shape</scene> when the insulin receptor is inactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a <scene name='83/839263/T-shape/4'>T-shape</scene>. An additional component to the [http://en.wikipedia.org/wiki/Ectodomain ectodomain] is <scene name='83/839263/Alpha-ct/2'> α-CT</scene>.<ref name= "Uchikawa" /> Each of the dimers has an α-CT helix. The α-CT helix is a single alpha-helix that plays an important role in insulin binding and stabilization of the "T" shape activated conformation. α-CT interacts with a leucine-rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form the insulin binding sites known as <scene name='83/839263/Insulin_molecules_at_site_1/1'>site 1 and site 1'</scene>.<ref name="Uchikawa" /><br />
<br />
The structure of the extracellular domain is stabilized through multiple [http://en.wikipedia.org/wiki/Disulfide disulfide bonds]. The alpha subunits are linked through two disulfide bonds, with the main one being between <scene name='83/839263/Cys_holding_alphas_together/4'>Cys524</scene> of two adjacent alpha subuntis <ref name="Schäffer" />. <scene name='83/839263/Cys_683_holding_alphas_togethe/3'>Cys683</scene> of both alpha subunits are also held together with a disulfide bond.<ref name="Sparrow"> PMID: 9368005</ref> The alpha subunit is also attached to the beta subunit by a disulfide bond between the <scene name='83/839263/Alpha_beta_link_by_disulfide/5'>Cys647 of the alpha subunit and Cys872 of the beta subunit</scene>.<ref name="Sparrow" /><br />
<br />
== Function==<br />
===Insulin Binding===<br />
The insulin receptor unit has four separate sites for the insulin binding. There are two pairs of two identical binding sites referred to as <scene name='83/839263/Insulin_molecules_at_site_1/1'>sites 1 and 1'</scene> and <scene name='83/839263/Insulin_molecules_at_site_2/1'>sites 2 and 2'</scene>. <br />
<br />
The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions], with some of the most crucial residues at sites 1 and 1' being between <scene name='83/839263/Residues_of_site_1_binding/8'>Cys A7, Cys B7, and His B5 of insulin and Pro495, Phe497, and Arg498</scene> of the insulin receptor FnIII-1 domain.<ref name="Uchikawa" /> Despite some of the residues included being charged, the main interactions are still hydrophobic in this binding site. For example, due to arginine carrying its positive charge at the end of the side chain, <scene name='83/839263/Arginine_bending/1'> the side chain is bent</scene> to allow the hydrophobic part of the side chain to interact with the other hydrophobic residues. The alpha subunits also have significant <scene name='83/832953/Cysteine_bond/3'>disulfide linkages</scene> that help maintain a compact binging site. At sites 2 and 2', the major residues contributing to these hydrophobic interactions are the <scene name='83/839263/Site_2_residues_hydrophobic/4'>Leu 486, Leu 552, and Pro537 of the insulin receptor and Leu A13, Try A14, Leu A16, Leu B6, Ala B14, Leu B17 and Val B18 of the insulin molecule</scene>.<ref name="Uchikawa" /> <br />
<br />
Sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site 1 having a larger surface area (706 Å<sup>2</sup>) exposed for insulin to bind to compared to site 2 (394 Å<sup>2</sup>).<ref name="Uchikawa" /> The binding interactions of the insulin molecules in sites 1 and 1' are facilitated by hydrophobic residues of an <scene name='83/839263/Insulin_bound_to_site_1/4'>alpha-helix</scene> of the insulin receptor. The insulin molecules in sites 2 and 2' primarily interact with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/7'>beta-sheets</scene> of the insulin receptor. <br />
[[Image:SurfaceIR.png|thumb|right|300px|Figure 3: Surface representation of the insulin receptor in the active "T" shape conformation with four insulins bound (green). [http://www.rcsb.org/structure/6SOF PDB 6SOF]]]<br />
At <scene name='83/832953/Sites_1_and_1_prime_location/17'>binding sites 1 and 1'</scene>, a <scene name='83/832953/Tripartite_interaction/8'>tripartite interaction</scene> occurs between three critical parts of the alpha subunits of the insulin receptor.<ref name="Uchikawa" /> The entire interface of the tripartite interaction involves many residues that are involved with intra-protomer ionic and hydrogen bonding at the binding site. The α-CT chain and the FnIII-1 domain region come into close proximity during the conformational change of the insulin receptor and their interaction involves the following residues: <scene name='83/832953/Alpha_ct_and_fniii-1/7'>ASP496, ARG498, and ASP499 on the FnIII-1 domain</scene> and the <scene name='83/832953/Alpha_ct_and_fniii-1/9'>LYS703, GLU706, and ASP707 on the α-CT domain</scene>. This duo then interacts with the L1 region, specifically ARG14, creating an ideal <scene name='83/832953/Tripartite_interaction/9'>binding site</scene> for the insulin ligand. The FnIII-1 and α-CT are interacting from the two different alpha subunits, which displays a "cross linking" scenario where the domains of the heterodimer can intertwine with each other. The tripartite interaction between α-CT, the FnIII-1 domain, and the L1 region is important because it allows for a strong interaction between two subunits of the insulin receptor that maintains and stabilizes the T-shape activation state for the rest of the downstream signaling to occur.<ref name="Uchikawa" /> <br />
<br />
It has been hypothesized that activation of the insulin receptor can change based on the concentration of insulin. These recent cryo-EM structures of the insulin receptor have demonstrated that at least three insulin molecules have to bind to the insulin receptor to induce the active <scene name='83/839263/T-shape/4'>T-shape</scene> conformation, as binding of two insulin molecules is insufficient to induce a full conformational change.<ref name="Uchikawa" /> However, this conclusion has not yet been widely confirmed.<ref name="Uchikawa" /> In low concentrations of insulin, the insulin receptor may not require binding of three insulin molecules in order to exhibit activation. Rather, the level of activity will change in accordance to the availability of insulin.<ref name="Uchikawa" /> When higher concentrations of insulin are present, the conformational difference between the two-insulin-bound state and the three-insulin-bound state is drastic as the insulin receptor transitions from the inactive <scene name='83/839263/V_shape/3'>V- shape</scene> to the active <scene name='83/839263/T-shape/4'>T-shape</scene>.<ref name="Uchikawa" /> However, in conditions of low insulin availability, the two-insulin-bound state may be enough to induce partial activation of the receptor.<ref name="Uchikawa" /><br />
<br />
===Conformational Changes===<br />
The conformational change between the inverted, inactive <scene name='83/839263/V_shape/3'>V-shape</scene> and the active <scene name='83/839263/T-shape/4'>T-shape</scene> of the insulin receptor is induced by insulin binding. The T shape conformation is well observed in the alpha subunit. It is horizontally composed of L1, CR (including the <scene name='83/832953/Alpha_c_helix/9'>α-CT chain</scene>), and L2 domains and vertically composed of the FnIII-1, 2, and 3 domains (Figure 1). The proper conformational change of the ectodomain of the insulin receptor is crucial for transmitting the signal into the cell. The movements extracellularly cause the two receptor tyrosine kinase domains intracellularly to become close enough to each other to [http://en.wikipedia.org/wiki/Autophosphorylation autophosphorylate].<ref name="Boucher" /> This autophosphorylation activates the tyrosine kinase domain, initiating intracellular insulin signaling cascades.<ref name="Boucher" /><br />
[[Image:image 6.png|thumb|right|300px|Figure 4: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding. [http://www.rcsb.org/structure/4ZXB Inactive PDB 4ZXB] [http://www.rcsb.org/structure/6SOF Active PDB 6SOF]]]<br />
When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the <scene name='83/839263/Fniii_domains/1'>Fibronectin type III domains</scene> of the beta subunit is initiated. This is accomplished by the formation of several [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges], specifically between <scene name='83/839263/Salt_bridges/1'>Arg498 and Asp499 of the FnIII-1 and Lys703, Glu706, and Asp707 of the alpha-CT</scene>.<ref name="Uchikawa" /> Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion as both protomers "swing" in towards one another.<ref name="Uchikawa" /> Figure 4 depicts the conformational change and "hinge motion" between the inactive and active forms of an insulin receptor protomer. Upon insulin binding, the beta subunits of the inactive form, shown in blue, are "swung" inward to the active form, shown in orange. When the receptor is in an <scene name='83/832953/Inactive_insulin_receptor/6'>inverted V shape</scene>, the FnIII-3 domains are separated by about 120Å.<ref name= "Mckern"> PMID: 16957736</ref> This distance prevents the initiation of autophosphorylation and downstream signaling by the tyrosine kinase domains on the intracellular side of the receptor. Upon the binding of insulin to multiple binding sites, this conformation change brings the FnIII-3 domains within 40Å of each other to induce the <scene name='83/832953/Ir_dimer_t_state/4'>T shape</scene> conformation.<ref name="Uchikawa" /> <ref> DOI 10.1038/s41467-018-06826-6</ref> As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine-rich region of one protomer interacts with α-CT and the FNIII-1 domains of the other protomer to form the <scene name='83/839263/Tripartite_interface/2'>tripartite interface</scene> binding site.<ref name="Uchikawa" /> For the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion. While snapshots of various conformational states of the insulin receptor have been captured, the complex dynamics of the insulin receptor conformational changes upon insulin binding are still being actively investigated.<ref name="Uchikawa" /><br />
<br />
== Receptor Tyrosine Kinase Domain Structure and Links ==<br />
<scene name='51/516456/Cv/8'>Human insulin receptor tyrosine kinase catalytic domain complex with insulin receptor substrate 2 peptide, Mg+2 ion and ATP</scene> (PDB entry [[3bu5]]).<br />
<br />
TK domain of IR contains an activation loop and a catalytic loop and <scene name='51/516456/Cv/7'>3 phosphorylated tyrosine residues</scene>. The bound IR substrate 2 peptide tyrosine is the phosphorylated residue<ref>PMID:18278056</ref>.<br />
<br />
In type 2 diabetes, the TK domain is thought to be down-regulated through phosphorylation of <scene name='51/516456/Thr1160/1'>threonine 1160</scene> by protein kinase C<ref>PMID:27760050</ref>.<br />
<br />
<scene name='51/516456/Cv/9'>ATP/Mg binding site</scene>. Water molecules shown as red spheres.<br />
<br />
See also [[Insulin Receptor - kinase domain (Hebrew)]] and [[Insulin receptor (Hebrew)]].<br />
<br />
The β-chain contains a tyrosine kinase catalytic domain (TK) residues 1005-1310. For more details see [[Student Projects for UMass Chemistry 423 Spring 2012-1]].<br />
<br />
==Biological Relevance==<br />
In a healthy individual, insulin secretion and binding to the insulin receptor initiates a robust physiological response. Improper insulin signaling leads to multiple disease states, including diabetes. [http://en.wikipedia.org/wiki/Type_1_diabetes Type 1 diabetes] is classified as "insulin dependent" and involves an inability for the body to produce insulin, resulting from damage or insufficiency in the Islets of Langerhans in the pancreas. [http://en.wikipedia.org/wiki/Type_2_diabetes Type 2 diabetes] is classified as "insulin independent" and is the result of the body producing insufficient amounts of insulin, or not responding to the insulin. <br />
<br />
===Type II Diabetes===<br />
[http://en.wikipedia.org/wiki/Type_2_diabetes Type II diabetes] (T2D) is a chronic condition that affects 10 percent of the world's population.<ref name="Boucher" /> T2D is characterized by insulin resistance and leads to high concentrations of glucose in the bloodstream. A type II diabetic produces insulin, but when the insulin molecule binds to the insulin receptor, the signal is not properly transmitted intracellularly. Insulin resistance in routine type II diabetics is not associated with mutations of the insulin receptor gene, but instead, the signal being disrupted later in the pathway. Mutations of the receptor gene are associated with more severe cases of insulin resistance, as seen in [http://en.wikipedia.org/wiki/Donohue_syndrome leprechaunism]. Additionally, mutations of the insulin receptor can be fatal, as it is crucial for many cellular processes including gene expression, glucose homeostasis, and apoptosis. The basis for insulin resistance in typical type II diabetics is complex and cannot yet be explained by one particular factor.<ref name="Boucher" /> <ref name="Franks"> DOI:10.1126/science.aaf5094</ref> <br />
<br />
There are a multitude of hypotheses which discuss the reasons for the establishment of type II diabetes.<ref name="Boucher" /> <ref name="Franks" /> While the specifics of the development of T2D are beyond the scope of this page, the molecular causes for insulin resistance and T2D have been primarily attributed to the inhibition of key proteins involved in the insulin signaling and glucose transport pathway.<ref name="Boucher" /> Alterations to the phosphorylation cascade of insulin signaling can be the result of changes within the cellular environment including [http://en.wikipedia.org/wiki/Lipotoxicity lipotoxicity], inflammation, [http://en.wikipedia.org/wiki/Hyperglycemia hyperglycemia], and the presence of [http://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] (ROS).<ref name="Boucher" /> On a macroscopic level, a variety of factors influence the cellular environment, and thus the risk for T2D. These factors include gestational environment, [http://en.wikipedia.org/wiki/Human_microbiome microbiome], genetics, diet, and energy expenditure.<ref name="Franks" /> Recent studies, which have evaluated the relationships between genetics and environmental factors in the progress of T2D, have shown that T2D is not uniform among the population and the biochemistry behind the development of risk factors varies for each patient.<ref name="Franks" /><br />
<br />
==3D structures of insulin receptor==<br />
[[Insulin receptor 3D structures]]<br />
<br />
</StructureSection><br />
<br />
== References ==<br />
<references/><br />
==Student Contributors==<br />
Abby Hillan<br />
<br />
Alyssa Ritter<br />
<br />
Andrew Scheel<br />
<br />
Harrison Smith<br />
<br />
Maxwell Todd<br />
[[Category:Topic Page]]<br />
[[Category:Featured in BAMBED]]</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Insulin_receptor&diff=4386078Insulin receptor2025-10-23T19:31:45Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{BAMBED<br />
|DATE=December 3, 2020<br />
|OLDID=3326280<br />
|BAMBEDDOI=10.1002/bmb.21560<br />
}}<br />
<br />
==Insulin Receptor==<br />
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulins Bound: (PDB Code [http://www.rcsb.org/pdb/explore/explore.do?structureId=6SOF 6SOF]). Alpha subunits in blue, beta subunits in orange, and 4 insulin molecules bound in green.' scene='83/839263/Intro_scene/2'><br />
<br />
==Function of the Receptor==<br />
The insulin receptor is a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] receptor that resides in the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] and is activated by the binding of insulin.<ref name="Meyts"/> The insulin receptor belongs to the large class of [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase] (RTKs). [[Receptor tyrosine kinases|RTKs]] are found at the cell surface and have a high affinity for a particular ligand. RTKs are made up of three distinct parts: an extracellular domain with ligand binding sites, a transmembrane region, and an intracellular domain with the tyrosine kinases that initiate intracellular signaling cascades.<ref name="Meyts"/><br />
<br />
The insulin receptor binds the [[insulin]] hormone and initiates a cascade of events within the cell. The receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin targeted cells. These cells are found in various organs, such as the liver, and tissues, including skeletal muscle and adipose.<ref name="Boucher"> PMID: 24384568</ref> The insulin receptor is activated by multiple insulin molecules binding to various sites on the receptor.<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref> Once activated, the receptor serves as the gateway for the regulation of various cellular processes including glucose transport, glycogen storage, [http://en.wikipedia.org/wiki/Autophagy autophagy], [http://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, problems with the insulin receptor are associated with the development of diseases such as Alzheimer's, type II diabetes, and cancer.<ref name="Scapin"> DOI:10.1038/nature26153</ref> <br />
<br />
Through recent [http://en.wikipedia.org/wiki/Transmission_electron_cryomicroscopy cryo-EM] structures of the insulin receptor bound in various conformations, a complete three-dimensional understanding of the conformational changes in the insulin receptor upon insulin binding are finally coming into focus. Evaluation of the structural composition and the biochemical properties of the insulin receptor reveals details about the role of the receptor in crucial cellular processes.<br />
<br />
See also [[Kinase-linked, enzyme-linked and related receptors]], [[Insulin signal transduction pathway]]<br><br />
<br />
<br />
==Insulin==<br />
<scene name='83/839263/Insulin_molecule/3'>Insulin</scene> is a [http://en.wikipedia.org/wiki/Hormone hormone] made of two separate amino acid chains that are bound by multiple disulfide bonds. Insulin is synthesized and secreted from the [http://en.wikipedia.org/wiki/Pancreatic_islets islets of Langerhans] of the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, insulin moves through the bloodstream and binds to unactivated insulin receptors residing in the plasma membrane. Binding of insulin to the insulin receptor is a complex process, which involves negative cooperativity among insulin molecules.<ref name="Meyts"> DOI:10.1007/BF00400837</ref> <ref name="Uchikawa" /> <ref name="Schäffer"> PMID: 1472036</ref> Current hypotheses propose that the receptor is fully activated only after multiple insulin molecules are bound.<ref name="Uchikawa" /> The binding of the increased amount of insulin to the insulin receptors will activate their downstream pathways to initiate glucose uptake by the phosphorylation of the [http://en.wikipedia.org/wiki/Insulin_receptor_substrate Insulin Receptor Substrate] (IRS).<ref name= "White"> PMID: 8276779</ref> The transport of extracellular glucose into the cell allows this glucose to be converted to [http://en.wikipedia.org/wiki/Glycogen glycogen] for storage and later usage.<br />
<br />
==Insulin Receptor Structural Overview==<br />
The insulin receptor is a [http://en.wikipedia.org/wiki/Dimer_(chemistry) dimer] of <scene name='83/839263/Alpha_and_beta_subunit/3'>heterodimers</scene> made of two <scene name='83/832953/Alpha_subunits/5'>alpha subunits</scene> and two <scene name='83/832953/Beta_subunits/4'>beta subunits</scene>. <ref name="Tatulian">PMID:26322622</ref> Within the extracellular ectodomain, there are four potential <scene name='83/832953/Binding_sites/3'>binding sites</scene> that can interact with insulin ligands on the extracellular side of the membrane. The full extracellular and intracellular components of the insulin receptor have only been imaged in separate sections but a larger picture of how these sections combine to initiate downstream tyrosine [http://en.wikipedia.org/wiki/Autophosphorylation autophosphorylation] is emerging.<ref name= "Hubbard"> DOI: 10.1093/emboj/16.18.5572 </ref><br />
<br />
===Alpha Subunits===<br />
[[Image:Harrison Image2.png|thumb|right|300px|Figure 1: Insulin receptor apo receptor. Site L1' is colored a dark green, CR' is orange, L2' is bright blue, L2 is yellow, CR is red, L1 is dark blue, FnIII-1 is brown, and FnIII-2 is light pink. Insulin is shown bound and is colored dark pink. [http://www.rcsb.org/structure/6CE7 PDB 6CE7]]]<br />
The <scene name='83/832953/Alpha_subunits/5'>alpha subunits</scene> make up the extracellular domain ([http://en.wikipedia.org/wiki/Ectodomain ectodomain]) of the insulin receptor and are the sites of insulin binding. The alpha subunit is comprised of two Leucine rich domains (L1 & L2), a Cysteine rich domain (CR), and a <scene name='83/832953/Alpha_c_helix/6'>an α-chain C-terminal helix (α-CT)</scene> (Figure 1).<ref name="Scapin"> PMID 29512653 </ref> α-CT has a unique position that allows it to reach across the receptor and interact with the insulin at the binding site on the opposing side of the receptor. The alpha subunits are held together by a [http://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='83/832953/Cysteine_bond/2'>cysteine residues</scene> on each alpha subunit. The disulfide bonds are important to the overall stabilization of the molecule as it binds to insulin. Two types of insulin binding sites are present in the alpha subunits, <scene name='83/832953/Sites_1_and_1_prime_location/17'>sites 1 and 1'</scene> and <scene name='83/832953/Sites_2_and_2_prime_location/13'>sites 2 and 2'</scene> (Figure 2). The sites are in pairs because of the heterodimeric nature of the receptor. Due to structural differences, as well as greater surface area and accessibility, binding sites 1 and 1' have much higher affinity for insulin binding than sites 2 and 2'. Insulin can also bind at sites 2 and 2', but the location on the back of the beta sheet of the FnIII-1 domain and lack of surface area decreases the likelihood of their binding site becoming occupied as quickly.<ref name="Uchikawa"> DOI 10.7554/eLife.48630 </ref> <br />
[[Image:4 sites highlighted - Harrison.png|thumb|right|300px|Figure 2: The four binding sites of insulin. Sites 1 and 1' are colored green, sites 2 and 2' are colored red. [http://www.rcsb.org/structure/6SOF PDB 6SOF]]]<br />
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===Beta Subunits===<br />
The <scene name='83/832953/Beta_subunits/4'>beta subunits</scene> spans from the extracellular domain across the transmembrane region and into the intracellular portion of the insulin receptor. The beta subunit is composed of part of [http://en.wikipedia.org/wiki/Fibronectin fibronectin] domain III-2 and all of Fibronectin domain III-3.<ref name="Scapin" /> The beta subunit's FnIII-3 domain has links through the transmembrane region into the intracellular part of the membrane. Cryo-EM provided clear representations of the FnIII-2 and FnIII-3 domains (Figure 1) but are missing the transmembrane and intracellular regions. Although the FnIII-3 domain is connected to the transmembrane and intracellular regions, the active <scene name='83/839263/T-shape/4'>T-shape</scene> conformation (Figure 3) likely extends all the way to the tyrosine kinase domain region (see [http://www.rcsb.org/structure/4XLV PDB 4XLV]).<ref name= "Cabail"> DOI: 10.1038/ncomms7406 </ref> <br />
<br />
===Subunit Organization===<br />
The alpha and beta subunits of the extracellular domains fold over one another and form a <scene name='83/839263/V_shape/3'>"V" shape</scene> when the insulin receptor is inactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a <scene name='83/839263/T-shape/4'>T-shape</scene>. An additional component to the [http://en.wikipedia.org/wiki/Ectodomain ectodomain] is <scene name='83/839263/Alpha-ct/2'> α-CT</scene>.<ref name= "Uchikawa" /> Each of the dimers has an α-CT helix. The α-CT helix is a single alpha-helix that plays an important role in insulin binding and stabilization of the "T" shape activated conformation. α-CT interacts with a leucine-rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form the insulin binding sites known as <scene name='83/839263/Insulin_molecules_at_site_1/1'>site 1 and site 1'</scene>.<ref name="Uchikawa" /><br />
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The structure of the extracellular domain is stabilized through multiple [http://en.wikipedia.org/wiki/Disulfide disulfide bonds]. The alpha subunits are linked through two disulfide bonds, with the main one being between <scene name='83/839263/Cys_holding_alphas_together/4'>Cys524</scene> of two adjacent alpha subuntis <ref name="Schäffer" />. <scene name='83/839263/Cys_683_holding_alphas_togethe/3'>Cys683</scene> of both alpha subunits are also held together with a disulfide bond.<ref name="Sparrow"> PMID: 9368005</ref> The alpha subunit is also attached to the beta subunit by a disulfide bond between the <scene name='83/839263/Alpha_beta_link_by_disulfide/5'>Cys647 of the alpha subunit and Cys872 of the beta subunit</scene>.<ref name="Sparrow" /><br />
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== Function==<br />
===Insulin Binding===<br />
The insulin receptor unit has four separate sites for the insulin binding. There are two pairs of two identical binding sites referred to as <scene name='83/839263/Insulin_molecules_at_site_1/1'>sites 1 and 1'</scene> and <scene name='83/839263/Insulin_molecules_at_site_2/1'>sites 2 and 2'</scene>. <br />
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The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions], with some of the most crucial residues at sites 1 and 1' being between <scene name='83/839263/Residues_of_site_1_binding/8'>Cys A7, Cys B7, and His B5 of insulin and Pro495, Phe497, and Arg498</scene> of the insulin receptor FnIII-1 domain.<ref name="Uchikawa" /> Despite some of the residues included being charged, the main interactions are still hydrophobic in this binding site. For example, due to arginine carrying its positive charge at the end of the side chain, <scene name='83/839263/Arginine_bending/1'> the side chain is bent</scene> to allow the hydrophobic part of the side chain to interact with the other hydrophobic residues. The alpha subunits also have significant <scene name='83/832953/Cysteine_bond/3'>disulfide linkages</scene> that help maintain a compact binging site. At sites 2 and 2', the major residues contributing to these hydrophobic interactions are the <scene name='83/839263/Site_2_residues_hydrophobic/4'>Leu 486, Leu 552, and Pro537 of the insulin receptor and Leu A13, Try A14, Leu A16, Leu B6, Ala B14, Leu B17 and Val B18 of the insulin molecule</scene>.<ref name="Uchikawa" /> <br />
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Sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site 1 having a larger surface area (706 Å<sup>2</sup>) exposed for insulin to bind to compared to site 2 (394 Å<sup>2</sup>).<ref name="Uchikawa" /> The binding interactions of the insulin molecules in sites 1 and 1' are facilitated by hydrophobic residues of an <scene name='83/839263/Insulin_bound_to_site_1/4'>alpha-helix</scene> of the insulin receptor. The insulin molecules in sites 2 and 2' primarily interact with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/7'>beta-sheets</scene> of the insulin receptor. <br />
[[Image:SurfaceIR.png|thumb|right|300px|Figure 3: Surface representation of the insulin receptor in the active "T" shape conformation with four insulins bound (green). [http://www.rcsb.org/structure/6SOF PDB 6SOF]]]<br />
At <scene name='83/832953/Sites_1_and_1_prime_location/17'>binding sites 1 and 1'</scene>, a <scene name='83/832953/Tripartite_interaction/8'>tripartite interaction</scene> occurs between three critical parts of the alpha subunits of the insulin receptor.<ref name="Uchikawa" /> The entire interface of the tripartite interaction involves many residues that are involved with intra-protomer ionic and hydrogen bonding at the binding site. The α-CT chain and the FnIII-1 domain region come into close proximity during the conformational change of the insulin receptor and their interaction involves the following residues: <scene name='83/832953/Alpha_ct_and_fniii-1/7'>ASP496, ARG498, and ASP499 on the FnIII-1 domain</scene> and the <scene name='83/832953/Alpha_ct_and_fniii-1/9'>LYS703, GLU706, and ASP707 on the α-CT domain</scene>. This duo then interacts with the L1 region, specifically ARG14, creating an ideal <scene name='83/832953/Tripartite_interaction/9'>binding site</scene> for the insulin ligand. The FnIII-1 and α-CT are interacting from the two different alpha subunits, which displays a "cross linking" scenario where the domains of the heterodimer can intertwine with each other. The tripartite interaction between α-CT, the FnIII-1 domain, and the L1 region is important because it allows for a strong interaction between two subunits of the insulin receptor that maintains and stabilizes the T-shape activation state for the rest of the downstream signaling to occur.<ref name="Uchikawa" /> <br />
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It has been hypothesized that activation of the insulin receptor can change based on the concentration of insulin. These recent cryo-EM structures of the insulin receptor have demonstrated that at least three insulin molecules have to bind to the insulin receptor to induce the active <scene name='83/839263/T-shape/4'>T-shape</scene> conformation, as binding of two insulin molecules is insufficient to induce a full conformational change.<ref name="Uchikawa" /> However, this conclusion has not yet been widely confirmed.<ref name="Uchikawa" /> In low concentrations of insulin, the insulin receptor may not require binding of three insulin molecules in order to exhibit activation. Rather, the level of activity will change in accordance to the availability of insulin.<ref name="Uchikawa" /> When higher concentrations of insulin are present, the conformational difference between the two-insulin-bound state and the three-insulin-bound state is drastic as the insulin receptor transitions from the inactive <scene name='83/839263/V_shape/3'>"V" shape</scene> to the active <scene name='83/839263/T-shape/4'>T-shape</scene>.<ref name="Uchikawa" /> However, in conditions of low insulin availability, the two-insulin-bound state may be enough to induce partial activation of the receptor.<ref name="Uchikawa" /><br />
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===Conformational Changes===<br />
The conformational change between the inverted, inactive <scene name='83/839263/V_shape/3'>"V" shape</scene> and the active <scene name='83/839263/T-shape/4'>T-shape</scene> of the insulin receptor is induced by insulin binding. The T shape conformation is well observed in the alpha subunit. It is horizontally composed of L1, CR (including the <scene name='83/832953/Alpha_c_helix/9'>α-CT chain</scene>), and L2 domains and vertically composed of the FnIII-1, 2, and 3 domains (Figure 1). The proper conformational change of the ectodomain of the insulin receptor is crucial for transmitting the signal into the cell. The movements extracellularly cause the two receptor tyrosine kinase domains intracellularly to become close enough to each other to [http://en.wikipedia.org/wiki/Autophosphorylation autophosphorylate].<ref name="Boucher" /> This autophosphorylation activates the tyrosine kinase domain, initiating intracellular insulin signaling cascades.<ref name="Boucher" /><br />
[[Image:image 6.png|thumb|right|300px|Figure 4: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding. [http://www.rcsb.org/structure/4ZXB Inactive PDB 4ZXB] [http://www.rcsb.org/structure/6SOF Active PDB 6SOF]]]<br />
When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the <scene name='83/839263/Fniii_domains/1'>Fibronectin type III domains</scene> of the beta subunit is initiated. This is accomplished by the formation of several [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges], specifically between <scene name='83/839263/Salt_bridges/1'>Arg498 and Asp499 of the FnIII-1 and Lys703, Glu706, and Asp707 of the alpha-CT</scene>.<ref name="Uchikawa" /> Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion as both protomers "swing" in towards one another.<ref name="Uchikawa" /> Figure 4 depicts the conformational change and "hinge motion" between the inactive and active forms of an insulin receptor protomer. Upon insulin binding, the beta subunits of the inactive form, shown in blue, are "swung" inward to the active form, shown in orange. When the receptor is in an <scene name='83/832953/Inactive_insulin_receptor/6'>inverted V shape</scene>, the FnIII-3 domains are separated by about 120Å.<ref name= "Mckern"> PMID: 16957736</ref> This distance prevents the initiation of autophosphorylation and downstream signaling by the tyrosine kinase domains on the intracellular side of the receptor. Upon the binding of insulin to multiple binding sites, this conformation change brings the FnIII-3 domains within 40Å of each other to induce the <scene name='83/832953/Ir_dimer_t_state/4'>T shape</scene> conformation.<ref name="Uchikawa" /> <ref> DOI 10.1038/s41467-018-06826-6</ref> As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine-rich region of one protomer interacts with α-CT and the FNIII-1 domains of the other protomer to form the <scene name='83/839263/Tripartite_interface/2'>tripartite interface</scene> binding site.<ref name="Uchikawa" /> For the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion. While snapshots of various conformational states of the insulin receptor have been captured, the complex dynamics of the insulin receptor conformational changes upon insulin binding are still being actively investigated.<ref name="Uchikawa" /><br />
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== Receptor Tyrosine Kinase Domain Structure and Links ==<br />
<scene name='51/516456/Cv/8'>Human insulin receptor tyrosine kinase catalytic domain complex with insulin receptor substrate 2 peptide, Mg+2 ion and ATP</scene> (PDB entry [[3bu5]]).<br />
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TK domain of IR contains an activation loop and a catalytic loop and <scene name='51/516456/Cv/7'>3 phosphorylated tyrosine residues</scene>. The bound IR substrate 2 peptide tyrosine is the phosphorylated residue<ref>PMID:18278056</ref>.<br />
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In type 2 diabetes, the TK domain is thought to be down-regulated through phosphorylation of <scene name='51/516456/Thr1160/1'>threonine 1160</scene> by protein kinase C<ref>PMID:27760050</ref>.<br />
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<scene name='51/516456/Cv/9'>ATP/Mg binding site</scene>. Water molecules shown as red spheres.<br />
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See also [[Insulin Receptor - kinase domain (Hebrew)]] and [[Insulin receptor (Hebrew)]].<br />
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The β-chain contains a tyrosine kinase catalytic domain (TK) residues 1005-1310. For more details see [[Student Projects for UMass Chemistry 423 Spring 2012-1]].<br />
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==Biological Relevance==<br />
In a healthy individual, insulin secretion and binding to the insulin receptor initiates a robust physiological response. Improper insulin signaling leads to multiple disease states, including diabetes. [http://en.wikipedia.org/wiki/Type_1_diabetes Type 1 diabetes] is classified as "insulin dependent" and involves an inability for the body to produce insulin, resulting from damage or insufficiency in the Islets of Langerhans in the pancreas. [http://en.wikipedia.org/wiki/Type_2_diabetes Type 2 diabetes] is classified as "insulin independent" and is the result of the body producing insufficient amounts of insulin, or not responding to the insulin. <br />
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===Type II Diabetes===<br />
[http://en.wikipedia.org/wiki/Type_2_diabetes Type II diabetes] (T2D) is a chronic condition that affects 10 percent of the world's population.<ref name="Boucher" /> T2D is characterized by insulin resistance and leads to high concentrations of glucose in the bloodstream. A type II diabetic produces insulin, but when the insulin molecule binds to the insulin receptor, the signal is not properly transmitted intracellularly. Insulin resistance in routine type II diabetics is not associated with mutations of the insulin receptor gene, but instead, the signal being disrupted later in the pathway. Mutations of the receptor gene are associated with more severe cases of insulin resistance, as seen in [http://en.wikipedia.org/wiki/Donohue_syndrome leprechaunism]. Additionally, mutations of the insulin receptor can be fatal, as it is crucial for many cellular processes including gene expression, glucose homeostasis, and apoptosis. The basis for insulin resistance in typical type II diabetics is complex and cannot yet be explained by one particular factor.<ref name="Boucher" /> <ref name="Franks"> DOI:10.1126/science.aaf5094</ref> <br />
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There are a multitude of hypotheses which discuss the reasons for the establishment of type II diabetes.<ref name="Boucher" /> <ref name="Franks" /> While the specifics of the development of T2D are beyond the scope of this page, the molecular causes for insulin resistance and T2D have been primarily attributed to the inhibition of key proteins involved in the insulin signaling and glucose transport pathway.<ref name="Boucher" /> Alterations to the phosphorylation cascade of insulin signaling can be the result of changes within the cellular environment including [http://en.wikipedia.org/wiki/Lipotoxicity lipotoxicity], inflammation, [http://en.wikipedia.org/wiki/Hyperglycemia hyperglycemia], and the presence of [http://en.wikipedia.org/wiki/Reactive_oxygen_species reactive oxygen species] (ROS).<ref name="Boucher" /> On a macroscopic level, a variety of factors influence the cellular environment, and thus the risk for T2D. These factors include gestational environment, [http://en.wikipedia.org/wiki/Human_microbiome microbiome], genetics, diet, and energy expenditure.<ref name="Franks" /> Recent studies, which have evaluated the relationships between genetics and environmental factors in the progress of T2D, have shown that T2D is not uniform among the population and the biochemistry behind the development of risk factors varies for each patient.<ref name="Franks" /><br />
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==3D structures of insulin receptor==<br />
[[Insulin receptor 3D structures]]<br />
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</StructureSection><br />
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== References ==<br />
<references/><br />
==Student Contributors==<br />
Abby Hillan<br />
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Alyssa Ritter<br />
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Andrew Scheel<br />
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Harrison Smith<br />
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Maxwell Todd<br />
[[Category:Topic Page]]<br />
[[Category:Featured in BAMBED]]</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=User:R._Jeremy_Johnson/Sandbox_1&diff=4325728User:R. Jeremy Johnson/Sandbox 12025-04-10T19:08:48Z<p>R. Jeremy Johnson: </p>
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<div><Structure load='7RSA' size='500' frame='true' align='right' caption='Ribonuclease A - Structure 7RSA' scene ='User:R._Jeremy_Johnson/Sandbox_1/Basic_ribonuclease/1' /><br />
<scene name='User:R._Jeremy_Johnson/Sandbox_1/Basic_ribonuclease/1'>Ribonuclease A - Structure 7RSA</scene><br />
[http://www.butler.edu]<br />
==Background==<br />
This structure of Photosystem II was crystallized from the cyanobacteria, ''Thermosynechococcus elongatus'', at 3.0Å <ref>Loll, B., Kern, J., Saenger, W., Zouni, A., Biesiadka, J., "Towards complete cofactor arrangement in the 3.0 A resolution structure of photosystem II." Nature, Dec 15, 2005, 438(7070), 1040-4. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16355230 16355230]</ref> and at 3.50 Å <ref>Ferreira, K.N., Iverson, T.M., Maghlaoui, K., Barber, J., Iwata, S. "Architecture of the photosynthetic oxygen-evolving center." Science, March 19, 2004, 303 (5665), 1831-8. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14764885 14764885]</ref>. PDB codes are [[2axt]] and [[1s5l]], respectively. Cyanobacteria and plants both contain Photosystem II while photosynthetic bacteria contain the bacterial reaction center. This photosynthetic protein complex is associated with a variety of functional ligands. It is a <scene name='Photosystem_II/Psii_dimer/1'>dimer</scene> composed mainly of alpha-helices. Nineteen <scene name='Photosystem_II/Protein_only/1'>subunits</scene> are in each monomer, with multiple extrinsic subunits associated with the oxygen evolving complex missing from this crystallization. Photosystem II is a membrane bound protein complex that in plants is associated with the thylakoid membrane of chloroplasts. <scene name='Photosystem_II/Hydrophobic_polar/1'>Polar and hydrophobic</scene> regions correlate with membrane associated nature of the protein. '''<FONT COLOR="#616D7E">Hydrophobic</FONT>''' helices make up the transmembranal portion, while '''<FONT COLOR="#C031C7">polar</FONT>''' residues are concentrated externally on either side of the membrane.<br />
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<ref>DOI: 10.1038/s41586-022-04845-4 </ref><br />
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<Ref> Asami J, Kimura KT, Fujita-Fujiharu Y, Ishida H, Zhang Z, Nomura Y, Liu K, Uemura T, Sato Y, Ono M, Yamamoto M, Noda T, Shigematsu H, Drew D, Iwata S, Shimizu T, Nomura N, Ohto U. Structure of the bile acid transporter and HBV receptor NTCP. Nature. 2022 Jun;606(7916):1021-1026. [https://dx.doi.org/10.1038/s41586-022-04845-4 DOI: 10.1038/s41586-022-04845-4]. </Ref><br />
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==Basic Structure==<br />
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<ref name = "Butler"> PMID: 7016210 </ref><br />
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<scene name='43/436107/Arginine_highlight/4'>Ver4</scene><br />
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<scene name='43/436107/Arginine_highlight/3'>Ver3</scene><br />
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<scene name='43/436107/Arginine_highlight/8'>Ver8</scene><br />
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<scene name='43/436107/Arginine_highlight/7'>Ver7</scene><br />
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<scene name='43/436107/Arginine_highlight/6'>Ver6</scene><br />
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<scene name='43/436107/Arginine_highlight/5'>Ver5</scene><br />
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<scene name='43/436107/Arginine_highlight/2'>Arginine Zoom</scene><br />
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==Electron Transfer==<br />
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<ref name= "Butler" /><br />
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4EB0 - Surface<br />
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Alignment and Chain Selection<br />
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==Basic Structure==<br />
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<ref>[http://www.butler.edu]</ref><br />
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==Additional Resources==<br />
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==References==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4316025Sandbox Reserved 18442025-03-20T20:23:42Z<p>R. Jeremy Johnson: </p>
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<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch Compost Bacterial Cutinase Homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
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<StructureSection load='4EB0' size='340' frame='true' side='right' caption='Leaf-branch compost bacterial cutinase homolog 4EB0' scene='10/1075246/Catalytic_triad/1'><br />
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==Introduction==<br />
<ref name="Sulaiman">PMID:24593046</ref>.<br />
== Function ==<br />
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===Active Site===<br />
[[Image:4EB0 Catalytic Triad.png |400 px |right| thumb|Figure 1. The coolest image of this protein EVAH!!!]] <br />
<scene name='10/1075246/Catalytic_triad2/1'>Catalytic Triad</scene><br />
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== Mechanism ==<br />
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== Relevance ==<br />
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== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
[https://www.rcsb.org/structure/4EB0 4EB0 PDB]<br />
<references/><br />
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==Student Contributors==<br />
*Rebecca Hoff<br />
*Name of Student</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1852&diff=4316024Sandbox Reserved 18522025-03-20T20:13:51Z<p>R. Jeremy Johnson: </p>
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<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Diels-Alderase ==<br />
<StructureSection load='4o5t' size='340' side='right' caption='Diels-Alderase 4o5t' scene=''><br />
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==Introduction==<br />
[https://www.pnas.org/doi/full/10.1073/pnas.1401073111 Impact of Scaffold Rigidity]<br />
== Structure==<br />
===Active Site===<br />
[[Image:BindingPocket.png|400px|right|thumb|Figure 1. The coolest image of this protein EVAH!!]]<br />
===Important Residues===<br />
Residues<scene name='10/1075254/Active_site/2'> Y134 and Q208</scene> are the important residues in the binding site. <br />
== Mechanism ==<br />
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== Relevance ==<br />
<ref name="Ransey">PMID:28504306</ref><br />
== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Contributors==<br />
Taylor Donahue<br />
Kate Thuma<br />
Micah Zile</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1852&diff=4316023Sandbox Reserved 18522025-03-20T20:10:27Z<p>R. Jeremy Johnson: </p>
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<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Diels-Alderase ==<br />
<StructureSection load='4o5t' size='340' side='right' caption='Diels-Alderase 4o5t' scene=''><br />
<br />
==Introduction==<br />
[https://www.pnas.org/doi/full/10.1073/pnas.1401073111 Impact of Scaffold Rigidity]<br />
== Structure==<br />
===Active Site===<br />
[[Image:BindingPocket.png|400px|right|thumb|Figure 1. The coolest image of this protein EVAH!!]]<br />
===Important Residues===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<ref name="Ransey">PMID:28504306</ref><br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Contributors==<br />
Taylor Donahue<br />
Kate Thuma<br />
Micah Zile</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1851&diff=4316012Sandbox Reserved 18512025-03-20T20:03:58Z<p>R. Jeremy Johnson: </p>
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<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Novel Diels-Alder Catalyst Identified Using ''de novo'' Design==<br />
<StructureSection load='4o5t' size='350' frame='true' side='right' caption='Diels-Alderase 4o5t' scene='10/1075253/Active_site_residues/1'><br />
==Introduction==<br />
[https://en.wikipedia.org/wiki/Diels%E2%80%93Alder_reaction Diels-Alder Reaction]<br />
==Function==<br />
===Stereoselectivity===<br />
<br />
==Mechanism==<br />
===Uncatalyzed Reaction===<br />
===Orbital Stabilization===<br />
<br />
==Structural Details==<br />
===Active Site===<br />
[[Image:N285toY134Mutant_(1).png|400 px|left|thumb|Figure 1. The coolest image of this protein EVAH!!!]]<br />
<scene name='10/1075253/Active_site_residues/2'>Active Site Residues</scene><br />
===Conserved Mutations===<br />
<br />
== Relevance ==<br />
===Chemical Applications===<br />
===Improvements===<br />
<br />
<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Collaborators==<br />
Micah Zile<br />
Kate Thuma<br />
Taylor Donahue</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1851&diff=4316010Sandbox Reserved 18512025-03-20T19:58:46Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Novel Diels-Alder Catalyst Identified Using ''de novo'' Design==<br />
<StructureSection load='4o5t' size='350' frame='true' side='right' caption='Diels-Alderase 4o5t' scene='10/1075253/Active_site_residues/1'><br />
==Introduction==<br />
[https://en.wikipedia.org/wiki/Diels%E2%80%93Alder_reaction Diels-Alder Reaction]<br />
==Function==<br />
===Stereoselectivity===<br />
<br />
==Mechanism==<br />
===Uncatalyzed Reaction===<br />
===Orbital Stabilization===<br />
<br />
==Structural Details==<br />
===Active Site===<br />
[[Image:N285toY134Mutant_(1).png|400 px|left|thumb|Figure 1. The coolest image of this protein EVAH!!!]]<br />
===Conserved Mutations===<br />
<br />
== Relevance ==<br />
===Chemical Applications===<br />
===Improvements===<br />
<br />
<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Collaborators==<br />
Micah Zile<br />
Kate Thuma<br />
Taylor Donahue</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4316007Sandbox Reserved 18472025-03-20T19:56:53Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein. <ref name="Longxing">PMID:32907861</ref>.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
This is the link to the salt bridge<br />
<scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene><br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4316004Sandbox Reserved 18472025-03-20T19:55:23Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein. <ref name="Ransey">PMID:28504306</ref>.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
This is the link to the salt bridge<br />
<scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene><br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4316002Sandbox Reserved 18442025-03-20T19:53:56Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch Compost Bacterial Cutinase Homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
<br />
<StructureSection load='4EB0' size='340' frame='true' side='right' caption='Leaf-branch compost bacterial cutinase homolog 4EB0' scene='<scene name='10/1075246/Catalytic_triad/1'>TextToBeDisplayed</scene>'><br />
<br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
===Active Site===<br />
[[Image:4EB0 Catalytic Triad.png |400 px |right| thumb|Figure 1. The coolest image of this protein EVAH!!!]] <br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
[https://www.rcsb.org/structure/4EB0 4EB0 PDB]<br />
<references/><br />
==Student Contributors==<br />
*Name of Student<br />
*Name of Student</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4316001Sandbox Reserved 18472025-03-20T19:53:54Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<ref name="Ransey">PMID:28504306</ref>.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
This is the link to the salt bridge<br />
<scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene><br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<ref name="Ransey">PMID:28504306</ref>.</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4316000Sandbox Reserved 18472025-03-20T19:51:10Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein. <ref name="Ransey"/><br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
This is the link to the salt bridge<br />
<scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene><br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<ref name="Ransey">PMID:28504306</ref>.</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315999Sandbox Reserved 18472025-03-20T19:49:36Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
This is the link to the salt bridge<br />
<scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene><br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<ref name="Ransey">PMID:28504306</ref>.</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315998Sandbox Reserved 18472025-03-20T19:44:39Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
This is the link to the salt bridge<br />
<scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene><br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315997Sandbox Reserved 18472025-03-20T19:43:26Z<p>R. Jeremy Johnson: </p>
<hr />
<div><scene name='10/1075249/Salt_bridge_lcb1/1'>10/1075249/Salt_bridge_lcb1/1</scene>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315996Sandbox Reserved 18472025-03-20T19:40:51Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='7JZU' size='340' side='right' caption='Caption for this structure' scene='10/1075249/Lcb1_spikerbd/1'><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315994Sandbox Reserved 18472025-03-20T19:37:18Z<p>R. Jeremy Johnson: </p>
<hr />
<div><Structure load='7JZU<scene name='10/1075249/Lcb1_spikerbd/1'>LCB1_SpikeRBD<scene name='10/1075249/Lcb1_spikerbd/1'>LCB_spikerbd<scene name='10/1075249/Lcb1_spikerbd/1'>Text To Be Displayed</scene></scene></scene>' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4315992Sandbox Reserved 18442025-03-20T19:37:13Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch Compost Bacterial Cutinase Homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
<br />
<StructureSection load='4EB0' size='340' frame='true' side='right' caption='Leaf-branch compost bacterial cutinase homolog 4EB0' scene=''><br />
<br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
===Active Site===<br />
[[Image:4EB0 Catalytic Triad.png |400 px |right| thumb|Figure 1. The coolest image of this protein EVAH!!!]] <br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
[https://www.rcsb.org/structure/4EB0 4EB0 PDB]<br />
<references/><br />
==Student Contributors==<br />
*Name of Student<br />
*Name of Student</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1851&diff=4315990Sandbox Reserved 18512025-03-20T19:36:33Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Novel Diels-Alder Catalyst Identified Using ''de novo'' Design==<br />
<StructureSection load='4o5t' size='350' frame='true' side='right' caption='Diels-Alderase 4o5t' scene=’’><br />
==Introduction==<br />
[https://en.wikipedia.org/wiki/Diels%E2%80%93Alder_reaction Diels-Alder Reaction]<br />
==Function==<br />
===Stereoselectivity===<br />
<br />
==Mechanism==<br />
===Uncatalyzed Reaction===<br />
===Orbital Stabilization===<br />
<br />
==Structural Details==<br />
===Active Site===<br />
[[Image:N285toY134Mutant_(1).png|400 px|left|thumb|Figure 1. The coolest image of this protein EVAH!!!]]<br />
===Conserved Mutations===<br />
<br />
== Relevance ==<br />
===Chemical Applications===<br />
===Improvements===<br />
<br />
<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Collaborators==<br />
Micah Zile<br />
Kate Thuma<br />
Taylor Donahue</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4315982Sandbox Reserved 18442025-03-20T19:30:55Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch Compost Bacterial Cutinase Homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
<br />
<StructureSection load='4EB0' size='340' frame='true' side='right' caption='Leaf-branch compost bacterial cutinase homolog 4EB0' scene=''><br />
<br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
===Active Site===<br />
[[Image:4EB0 Catalytic Triad.png | thumb]] <br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
==Student Contributors==<br />
*Name of Student<br />
*Name of Student</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:4EB0_Catalytic_Triad.png&diff=4315978File:4EB0 Catalytic Triad.png2025-03-20T19:27:07Z<p>R. Jeremy Johnson: Picture of 4EB0 Catalytic Triad and Ligand</p>
<hr />
<div>Picture of 4EB0 Catalytic Triad and Ligand</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1852&diff=4315974Sandbox Reserved 18522025-03-20T19:24:09Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Diels-Alderase ==<br />
<StructureSection load='4o5t' size='340' side='right' caption='Diels-Alderase 4o5t' scene=''><br />
<br />
==Introduction==<br />
[https://www.pnas.org/doi/full/10.1073/pnas.1401073111 Impact of Scaffold Rigidity]<br />
== Structure==<br />
===Active Site===<br />
[[Image:BindingPocket.png|400px|right|thumb|Figure 1. The coolest image of this protein EVAH!!]]<br />
===Important Residues===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Contributors==<br />
Taylor Donahue<br />
Kate Thuma<br />
Micah Zile</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1852&diff=4315971Sandbox Reserved 18522025-03-20T19:20:52Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Diels-Alderase ==<br />
<StructureSection load='4o5t' size='340' side='right' caption='Diels-Alderase 4o5t' scene=''><br />
<br />
==Introduction==<br />
<br />
== Structure==<br />
===Active Site===<br />
[[Image:BindingPocket.png|400px|right|thumb|Figure 1. The coolest image of this protein EVAH!!]]<br />
===Important Residues===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Contributors==<br />
Taylor Donahue<br />
Kate Thuma<br />
Micah Zile</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:N285toY134Mutant_(1).png&diff=4315969File:N285toY134Mutant (1).png2025-03-20T19:17:32Z<p>R. Jeremy Johnson: This shows the effect of an A-N mutation at residue 285, resulting in the stabilization of the active site residue Y134 near the substrate.</p>
<hr />
<div>This shows the effect of an A-N mutation at residue 285, resulting in the stabilization of the active site residue Y134 near the substrate.</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315968Sandbox Reserved 18472025-03-20T19:17:27Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image of LCB1 bound to the RBD of a spike protein.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315967Sandbox Reserved 18472025-03-20T19:16:45Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image I am including for practice.<br />
[[Image:LCB1 RBD.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:LCB1_RBD.png&diff=4315966File:LCB1 RBD.png2025-03-20T19:16:13Z<p>R. Jeremy Johnson: </p>
<hr />
<div></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:BindingPocket.png&diff=4315965File:BindingPocket.png2025-03-20T19:16:10Z<p>R. Jeremy Johnson: </p>
<hr />
<div></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4315964Sandbox Reserved 18442025-03-20T19:15:44Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch Compost Bacterial Cutinase Homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
<br />
<StructureSection load='4EB0' size='340' frame='true' side='right' caption='Leaf-branch compost bacterial cutinase homolog 4EB0' scene=''><br />
<br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
===Active Site===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
==Student Contributors==<br />
*Name of Student<br />
*Name of Student</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:4o1tSurface.png&diff=4315961File:4o1tSurface.png2025-03-20T19:12:53Z<p>R. Jeremy Johnson: </p>
<hr />
<div></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315958Sandbox Reserved 18472025-03-20T19:09:40Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image I am including for practice.<br />
[[Image:Helix amphipathic.png|400 px|left|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4315956Sandbox Reserved 18442025-03-20T19:09:11Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch compose bacterial cutinase homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
<br />
<StructureSection load='4EB0' size='340' side='right' caption='Caption for this structure' scene=''><br />
<br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
===Active Site===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
==Student Contributors==<br />
*Name of Student<br />
*Name of Student</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1852&diff=4315955Sandbox Reserved 18522025-03-20T19:09:09Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Diels-Alderase ==<br />
<StructureSection load='4o5t' size='340' side='right' caption='Diels-Alderase 4o5t' scene=''><br />
<br />
==Introduction==<br />
<br />
== Structure==<br />
===Active Site===<br />
===Important Residues===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Contributors==<br />
Taylor Donahue<br />
Kate Thuma<br />
Micah Zile</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315954Sandbox Reserved 18472025-03-20T19:08:39Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image I am including for practice.<br />
[[Image:Helix amphipathic.png|400 px|right|thumb|Figure 1. The coolest image ever!]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315953Sandbox Reserved 18472025-03-20T19:07:51Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image I am including for practice.<br />
[[Image:Helix amphipathic.png|100 px|left|thumb|Figure legend]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4315952Sandbox Reserved 18442025-03-20T19:07:30Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch compose bacterial cutinase homolog in uncultured bacterium''=<br />
<br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
<br />
<StructureSection load='4EB0' size='340' side='right' caption='Caption for this structure' scene=''><br />
<br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315951Sandbox Reserved 18472025-03-20T19:06:51Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
This is an image I am including for practice.<br />
[[Image:Helix amphipathic.png]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1852&diff=4315949Sandbox Reserved 18522025-03-20T19:05:59Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
==Diels-Alderase ==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
<br />
==Introduction==<br />
<br />
== Structure==<br />
===Active Site===<br />
===Important Residues===<br />
<br />
== Mechanism ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/><br />
<br />
==Student Contributors==<br />
Taylor Donahue<br />
Kate Thuma<br />
Micah Zile</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1844&diff=4315948Sandbox Reserved 18442025-03-20T19:05:54Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Leaf-branch compose bacterial cutinase homolog in uncultured bacterium''=<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Rebecca Hoff/Sandbox1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<StructureSection load=......><br />
==Introduction==<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:Helix_amphipathic.png&diff=4315944File:Helix amphipathic.png2025-03-20T19:00:03Z<p>R. Jeremy Johnson: This is a picture of a random helix.</p>
<hr />
<div>This is a picture of a random helix.</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1847&diff=4315938Sandbox Reserved 18472025-03-20T18:53:14Z<p>R. Jeremy Johnson: </p>
<hr />
<div>{{Sandbox_Reserved_CH462_Biochemistry_II_2025}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=''Structure''=<br />
==Subheading 1==<br />
===Sub-subheading 1===<br />
==Subheading 2==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page ''''''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
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</StructureSection><br />
== References ==<br />
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== Function ==<br />
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== References ==<br />
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== References ==<br />
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== Function ==<br />
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<scene name='72/727778/5nj3_loaded_bymyself/1'>Test Link for Julia</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/4'>Test Class 2</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/5'>Test 4-11</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/6'>Test 4-13</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/7'>Test 4 14</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/8'> Test 4 15</scene><br />
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== Disease ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=User:R._Jeremy_Johnson/Sandbox_4&diff=3752762User:R. Jeremy Johnson/Sandbox 42023-04-14T16:08:35Z<p>R. Jeremy Johnson: </p>
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== Function ==<br />
<scene name='72/721541/Hydrogen_binding_1/2'>TextToBeDisplayed</scene><br />
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'''<FONT COLOR="#C031C7">polar</FONT>'''<br />
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<scene name='72/727778/5nj3_loaded_bymyself/1'>Test Link for Julia</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/3'>TextToBeDisplayed</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/4'>Test Class 2</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/5'>Test 4-11</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/6'>Test 4-13</scene><br />
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<scene name='72/727778/5nj3_loaded_bymyself/7'>Test 4 14</scene><br />
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== Disease ==<br />
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== Structural highlights ==<br />
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
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</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1767&diff=3752675Sandbox Reserved 17672023-04-13T15:13:19Z<p>R. Jeremy Johnson: </p>
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<div>{{Template:CH462_Biochemistry_II_2023}}<!-- PLEASE ADD YOUR CONTENT BELOW HERE --><br />
=SHOC2-PP1C-MRAS=<br />
<StructureSection load='1stp' size='340' side='right' caption='SHOC2-MRAS-PP1C Holophosphatase Complex' scene='95/952694/Overall_image/2'><br />
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== Introduction ==<br />
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<scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for MAPK signaling.<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-Ras pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952695/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952695/Pp1cintro/3'>The PP1C subunit</scene> contains the the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> WRITE ABOUT RAF HERE Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref> <br />
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There are many regulatory mechanisms that serve as a lock on this RAS-MAPK pathway, decreasing the likelihood of unintentional pathway activation. One is a protein dimer called 14-3-3 that keeps inactive RAF localized to the cytoplasm. An N-terminal phosphorylated serine (NTpS) keeps RAF bound to this protein dimer, and when the SMP complex is assembled, the catalytic subunit, PP1C, removes the phosphate group from the serine residue, releasing RAF from the 14-3-3 dimer, and activating the RAS-MAPK cell proliferation pathway. <br />
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In all images and animations, {{Font color|cyan|SHOC2}} will be shown as cyan blue, {{Font color|lime|MRAS}} as lime, and {{Font color|violet|PP1C}} as violet. Other important components involved in the function of the SMP complex include the {{Font color|salmon|14-3-3}} dimer and {{Font color|slate-blue|Raf}}, which will be shown in salmon and slate-blue, respectively. <br />
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== Structure of Subunits == <br />
=== SHOC2 ===<br />
The presence of SHOC2 is essential for complex formation. It a crescent shaped complex that serves as a bridge for PP1C and MRAS, maximizing interaction between the three subunits of the SMP complex. SHOC2 contains a large leucine rich region (LRR) that provides stability and localizes subunit PP1C to the membrane. Houseman SHOC2 only undergoes a <scene name='95/952693/Shoc2_gtp_bound_vs_gdp_bound/7'>6° conformational change</scene> when PP1C and MRAS bind, showing SHOC2 is a scaffolding protein that provides a favorable interface for complex formation. SHOC2 depletion is being studied as a therapeutic approach for RAS-driven cancers due to large scale interactions of the subunits being made possible by SHOC2. <ref name="Kwon">PMID: 35831509</ref>. SHOC2 and PP1C first engage in binding with each other via an N-terminal RVXF motif on SHOC2 that is complimentary to a sequence on PP1C. SHOC2 residues V64 and F66 '''GREEN LINK?''' embed in the complimentary region of PP1C, enhancing SHOC2 affinity for PP1C. SHOC2 bind MRAS-GTP through β strands of a LRR that interacts with a hydrophobic region of MRAS-GTP further stabilizing the complex. KWON<br />
=== PP1C ===<br />
The Protein phosphatase complex 1 (PP1C) subunit contains the catalytic site of the SMP complex. The PP1C subunit is a phosphatase enzyme responsible for the removal of a phosphate group on the N-terminal phosphoserine (NTpS) of RAF (Ser259).<ref name="Liau">PMID: 35768504</ref>. The exact mechanism of dephosphorylation is currently unknown, but there are three catalytic metal ions: 2 Mn2+ and 1 Cl- present that coordinate nucleophilic water molecules in the active site. This dephosphorylation event allows for pathway activation. Although PP1C can dephosphorylate other proteins independently from the SMP complex, it cannot act on Raf unless bound to the complex because it lacks intrinsic substrate selectivity.<ref name="Liau">PMID: 35768504</ref> SHOC2 and MRAS aid in the specificity of the enzymatic activity. Hence, PP1C requires the presence of SHOC2 and MRAS to be function. <ref name="Hauseman">PMID:35830882</ref> PP1C binds to SHOC2 and MRAS-GTP in a specific orientation that doesn’t change the conformation of the catalytic site and leaves it accessible for substrate binding.<br />
PP1C binds to SHOC2 through a hydrophobic n-terminal disordered region that is complimentary to the RVXF motif on SHOC2. GREEN LINK or picture? Similarly to SHOC2, PP1C does not undergo a significant conformational change when SHOC2 and MRAS-GTP bind. The lack of conformational change shows that the structure of PP1C is not dependent on the SMP complex, but in order to act as a phosphatase it must be bound to the complex.<ref name="Liau">PMID: 35768504</ref>. <br />
PP1C binds to SHOC2 and MRAS-GTP in a specific orientation that doesn’t change the conformation of the catalytic site and leaves it accessible for substrate binding. '''GREEN LINK or picture?'''<br />
The substrate binds through hydrogen bonds with the main chain and side chain atoms of the catalytic residues **insert residue numbers here**. Mutations in the active site lead to increased activity, causing the Ras/Raf signaling cascade to be triggered more frequently.<ref name="Hurley">PMID: 17636256</ref> ***insert what residues are mutated and HOW it leads to more activity. <br />
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PP1C activity is regulated by short linear interaction motifs or PP1C-binding regulatory proteins.<ref name="Hauseman">PMID:35830882</ref> The regulatory proteins bind to small linear motifs in PP1C, like RVXF.<ref name="Liau">PMID: 35768504</ref> The RVXF motif and interaction site is located in PP1C through the N-terminal disordered region, which <ref name="Kwon">PMID: 35831509</ref> There is a direct interaction between the RVXF motif of SHOC2 and the hydrophobic RVXF-binding pocket of PP1C.<ref name="Hauseman">PMID:35830882</ref><ref name="Kwon">PMID: 35831509</ref> This hydrophobic binding site is adjacent to the catalytic metal ions. In the Ras/Raf signaling cascade, the region of Raf that is C-terminal to the phosphate group binds to this hydrophobic groove, and the remaining residues bind to the hydrophobic region of SHOC2. Raf binding to this region of SHOC2 is what allows PP1C to be specific when in the SMP complex in comparison to PP1C on its own. PP1C also has a singular cysteine (C291) present in the hydrophobic binding site in order to provide further stability to the substrate-protein interaction by forming a covalent bond to the substrate. <br />
PP1C is involved in many different cellular signaling pathways including protein synthesis, muscle contraction, and even carbohydrate metabolism. Wolfgang In all these pathways, including the SMP pathway, PP1C does not exist as a monomer, it is present in holoenzyme form complex with one of two regulatory subunits ensuring there is no sporadic pathway activation. Schulman <br />
===RAS/RAF ===<br />
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[[Image:pic3.jpg|250 px|right|thumb|Figure 1: MRAS binding sites with SHOC2, PP1C, and RAF (PDB 7DSO).<ref name="Liau">PMID: 35768504</ref>.]]<br />
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==RAF==<br />
While RAF is not technically part of the SMP protein complex, it is crucial for advancement in the cell signaling pathway SMP helps mediate. RAF plays many different roles in this pathway and has many different domains. RAF has a RAS binding domain (RBD), a N-terminal phosphorylated serine (NTpS), and a kinase domain. Figure ?? shows these domains and mechanistically how RAF is involved in signal advancement or lack thereof. When its N-terminal serine is phosphorylated RAF is bound to a 14-3-3 protein dimer, inactivating the pathway. Whenever the SMP complex is assembled, PP1C dephosphorylates this serine starting the signaling cascade. <br />
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==RAS==<br />
RAS proteins are GTP-dependent intracellular switches that are anchored to the plasma membrane. .<ref name="Liau">PMID: 35768504</ref> RAS proteins activate RAF kinases through direct binding and membrane recruitment, resulting in RAF dimerization and pathway activation. <ref name="Liau">PMID: 35768504</ref>. The SMP complex has specificity for MRAS. Other RAS proteins may bind to SHOC2, but MRAS induces the complex formation with a significantly lower Kd (dissociation constant).<ref name="Liau">PMID: 35768504</ref> There are no known membrane interacting regions on SHOC2 and PP1C, meaning the hydrophobic fatty acid tail on MRAS is responsible for recruiting the complex to the cell membrane .<ref name="Hauseman">PMID:35830882</ref>. <br />
A significant amount of steric overlap is seen in MRAS for the binding sites of PP1C, SHOC2, and Raf. In figure 1, MRAS is shown in green, with the SHOC2 binding site colored cyan, the PP1C binding site colored green, and the RAF binding site shown in red on a different RAS protein. Hence, multiple RAS proteins are required for further activation of the receptor tyrosine kinase pathway. Due to the significant overlap in binding domains, one MRAS molecule is needed to recruit SHOC2 and PP1C to the membrane, and another RAS molecule is needed activate RAF. The ability of scene name='95/952694/Cell_membrane/3'>MRAS-GTP to cluster at the cell membrane</scene> is a crucial capability for this protein complex. The presence of this scene name='95/952694/Cell_membrane/3'>palmitoyl tail on RAS </scene>is responsible for this anchoring to the cell membrane, similar to the hydrophobic fatty acid tail on MRAS that is responsible for recruiting SMP to the cell membrane, allowing only for 2D movement and increasing local concentrations of the players needed in this signaling pathway. .<ref name="Hauseman">PMID:35830882</ref><br />
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MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP. <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS lead to consistent GTP-loading, causing an increase in the formation of the SMP complex and there is consistent activation of the cell-proliferation pathway in the absence of external growth factors.<br />
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===Auto-inhibition===<br />
[[Image:MECH.png|500 px|center|thumb|Figure 3: Mechanism of SMP complex formation and activation of RAF.<ref name="Liau">PMID: 35768504</ref>.]]<br />
The Ras-Raf signaling cascade will be inhibited without the dephosphorylation of Raf at Ser259. There is a <scene name='95/952695/14-3-3/1'>14-3-3</scene> dimer present in the cytoplasm that interacts with Raf through hydrogen bonds between R129 of 14-3-3 and Ser259 of Raf when Ser259 is phosphorylated. This interaction causes an <scene name='95/952695/Autoinhibited_confirmation/7'>autoinhibited confirmation</scene> as 14-3-3 restricts Raf to the cytoplasm and sterically inhibits Raf from binding with activated Ras. This interaction is crucial in regulating cell proliferation, as it prevents cell growth in the absence of a signal. Extracellular growth factors trigger GTP to bind to MRAS, which triggers SMP formation. Upon SMP complex formation, PP1C is brought into close proximity of Ras, leading to the dephosphorylation of Ser259 of Raf by the active site of PP1C. Once dephosphorylated, Raf is in the <scene name='95/952695/Non-inhibited_confirmation/9'>active confirmation</scene>, allowing for the interaction of Ras and Raf, and the initiation of the signaling cascade.<ref name="Young">PMID: 30348783</ref><br />
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=== Switch I and Switch II ===<br />
[[Image:RASRAF.png|400 px|right|thumb|Figure 2: MRAS SWI and SWII open and closed conformations.<ref name="Liau">PMID: 35768504</ref>.]]<br />
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SHOC2-PP1C-MRAS is a central gatekeeper in receptor tyrosine kinase signaling 1. Figure 1 shows the specific pathways SHOC2-PP1C-MRAS mediates. When MRAS is bound to GDP, shown in the left of figure 1, Raf is bound to a 14-3-3 protein dimer restricting it to the cytoplasm. When MRAS-GDP is exchanged for GTP via a nucleotide exchange factor GEF, a conformational change occurs. This change, shown in figure 2, causes a shift from the <scene name='95/952693/Swi_open_conformation/6'>open conformation</scene> to <scene name='95/952693/Switch_i_gtp_bound/11'>closed conformation</scene> of Switch I. fThe Switch I (SWI) region is made up of residues 42-48 of the MRAS domain. 1 These residues are crucial for the binding of MRAS, SHOC2, and PP1C because MRAS undergoes a conformational change that allows for SMP complex assembly upon GTP binding. When GTP is bound to MRAS, it is in the “closed conformation” because hydrogen bond interactions between the γ phosphate of GTP and residues in the SWI region of MRAS cause SWI to adopt a closed conformation, as seen in figure 2. The closed conformation allows for the binding of SHOC2 and PP1C because there is no steric clash between the scene name='95/952693/Switch_i_gtp_bound/11'>SWI region of MRAS</scene> and the surface of SHOC2 when GTP is bound. The only large-scale conformational change occurs in the MRAS subunit. When GDP is bound to the MRAS domain, it is in the “open” conformation. Since the γ-phosphate is not bound to GDP, there are no hydrogen bond interactions with the oxygens of the γ-phosphate group and the MRAS SWI region, causing MRAS to adpot an "open" conformation. Since SHOC2 and PP1C do not undergo much conformational change, they are in a slow equilibrium of binding and unbinding until MRAS binds to GTP allowing MRAS to bind to SHOC2 and PP1C. <br />
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===Cancer and Rasopathies=== should we intersperse this?<br />
Common mutations in SHOC2 and PP1C lead to amino acid changes on the interaction surfaces, that can lead to higher binding affinity.<ref name="Lavoie">PMID: 35970881</ref>The interface of SHOC2-PP1C is stabilized by the Q249K mutation because this creates a salt bridge with E116 of PP1C. This enhances the binding energy by -22.7 kcal/mol. The G63R mutation on SHOC2 creates two additional hydrogen bonds with D242 on PP1C, released an additional 18.88kcal/mol of interaction energy.<ref name="Kwon">PMID: 35831509</ref> Mutations to MRAS can result in consistent GTP-loading, increasing the formation of the SMP complex in the absence of external growth factors that are necessary for activation of the pathway in a healthy organism. The majority of wild type MRAS in cells were in the GDP state, whereas the MRAS with the Q71R mutation locked in GTP-induced RAS conformational changes.<ref name="Hauseman">PMID:35830882</ref><br />
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MRAS G23V (equivalent to the oncogenic G13V in RAS), like MRAS Q71L (Q61L in RAS), also shows increased interaction with other effectors such as BRAF, CRAF, and AF6 (Fig. 6C), consistent with activating mutations leading to GTP-loading of MRAS (13). '''(THIS WILL BE A GREEN LINK)'''<br />
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Mutations in PP1C can trigger increased active site activity, increasing the RAF proteins that are active and available to bind to RAS. In patients with Noonan Syndrome, a disease in the rasopathy family, point mutations G23V and T68I in MRAS were identified, however, the outcome of these is unknown.<ref name="Young">PMID: 30348783</ref> Universally, when this MAPK cascade is unregulated, cells are able to proliferate regardless of external signals, leading to cancer and/or RASopathies. <br />
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</StructureSection><br />
== Protopedia Resources ==<br />
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== References ==<br />
<references/><br />
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1. Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Mollé S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA. Structure of the MRAS-SHOC2-PP1C phosphatase complex. Nature. 2022 Sep;609(7926):416-423. doi: [https://www.nature.com/articles/s41586-022-05086-1 10.1038/s41586-022-05086-1.] Epub 2022 Jul 13. PMID: [https://pubmed.ncbi.nlm.nih.gov/35830882/ 35830882]; PMCID: PMC9452295.<ref name="Hauseman">PMID:35830882</ref>.<br />
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2. Hurley TD, Yang J, Zhang L, Goodwin KD, Zou Q, Cortese M, Dunker AK, DePaoli-Roach AA. Structural basis for regulation of protein phosphatase 1 by inhibitor-2. J Biol Chem. 2007 Sep 28;282(39):28874-28883. doi: [https://www.sciencedirect.com/science/article/pii/S0021925820586201?via%3Dihub 10.1074/jbc.M703472200]. Epub 2007 Jul 18. PMID: [https://pubmed.ncbi.nlm.nih.gov/17636256/ 17636256].<ref name="Hurley">PMID: 17636256</ref>.<br />
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3. Kwon JJ, Hajian B, Bian Y, Young LC, Amor AJ, Fuller JR, Fraley CV, Sykes AM, So J, Pan J, Baker L, Lee SJ, Wheeler DB, Mayhew DL, Persky NS, Yang X, Root DE, Barsotti AM, Stamford AW, Perry CK, Burgin A, McCormick F, Lemke CT, Hahn WC, Aguirre AJ. Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature. 2022 Sep;609(7926):408-415. doi: [https://www.nature.com/articles/s41586-022-04928-2 10.1038/s41586-022-04928-2]. Epub 2022 Jul 13. PMID: [https://pubmed.ncbi.nlm.nih.gov/35831509/ 35831509]; PMCID: PMC9694338.<ref name="Kwon">PMID: 35831509</ref>.<br />
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4. Liau NPD, Johnson MC, Izadi S, Gerosa L, Hammel M, Bruning JM, Wendorff TJ, Phung W, Hymowitz SG, Sudhamsu J. Structural basis for SHOC2 modulation of RAS signalling. Nature. 2022 Sep;609(7926):400-407. doi: [https://www.nature.com/articles/s41586-022-04838-3 10.1038/s41586-022-04838-3]. Epub 2022 Jun 29. PMID: [https://pubmed.ncbi.nlm.nih.gov/35768504/ 35768504]; PMCID: PMC9452301.<ref name="Liau">PMID: 35768504</ref>.<br />
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5. Lavoie H, Therrien M. Structural keys unlock RAS-MAPK cellular signalling pathway. Nature. 2022 Sep;609(7926):248-249. doi: [https://www.nature.com/articles/d41586-022-02189-7 10.1038/d41586-022-02189-7]. PMID: [https://pubmed.ncbi.nlm.nih.gov/35970881/ 35970881].<ref name="Lavoie">PMID: 35970881</ref>.<br />
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6. Young LC, Hartig N, Boned Del Río I, Sari S, Ringham-Terry B, Wainwright JR, Jones GG, McCormick F, Rodriguez-Viciana P. SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10576-E10585. doi: [https://www.pnas.org/doi/full/10.1073/pnas.1720352115 10.1073/pnas.1720352115]. Epub 2018 Oct 22. PMID: [https://pubmed.ncbi.nlm.nih.gov/30348783/ 30348783]; PMCID: PMC6233131.<ref name="Young">PMID: 30348783</ref>.<br />
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== Student Contributors ==<br />
- Sloan August<br />
<br />
- Rosa Trippel<br />
<br />
- Kayla Wilhoite</div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=User:R._Jeremy_Johnson/Sandbox_4&diff=3752652User:R. Jeremy Johnson/Sandbox 42023-04-13T13:36:26Z<p>R. Jeremy Johnson: </p>
<hr />
<div>==Your Heading Here (maybe something like 'Structure')==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''R. Jeremy Johnson/Sandbox 4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<scene name='72/721541/Hydrogen_binding_1/2'>TextToBeDisplayed</scene><br />
<br />
'''<FONT COLOR="#C031C7">polar</FONT>'''<br />
<br />
<FONT COLOR="#C031C7">polar</FONT><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/1'>Test Link for Julia</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/2'>TextToBeDisplayed</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/3'>TextToBeDisplayed</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/4'>Test Class 2</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/5'>Test 4-11</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/6'>Test 4-13</scene><br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=User:R._Jeremy_Johnson/Sandbox_4&diff=3749003User:R. Jeremy Johnson/Sandbox 42023-04-11T11:36:01Z<p>R. Jeremy Johnson: </p>
<hr />
<div>==Your Heading Here (maybe something like 'Structure')==<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''R. Jeremy Johnson/Sandbox 4'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
== Function ==<br />
<scene name='72/721541/Hydrogen_binding_1/2'>TextToBeDisplayed</scene><br />
<br />
'''<FONT COLOR="#C031C7">polar</FONT>'''<br />
<br />
<FONT COLOR="#C031C7">polar</FONT><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/1'>Test Link for Julia</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/2'>TextToBeDisplayed</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/3'>TextToBeDisplayed</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/4'>Test Class 2</scene><br />
<br />
<scene name='72/727778/5nj3_loaded_bymyself/5'>Test 4-11</scene><br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>R. Jeremy Johnsonhttps://proteopedia.org/index.php?title=File:CS17_Veronika.pdb&diff=3748904File:CS17 Veronika.pdb2023-04-10T19:36:31Z<p>R. Jeremy Johnson: </p>
<hr />
<div></div>R. Jeremy Johnson