Proteopedia - User contributions [en]

Proteopedia:What's New

2010-05-02T03:50:11Z

Cinting Lim:

<big><b>What's New in Proteopedia?</b></big>
<br>
This page lists new pages, substantially updated pages, and new capabilities '''within''' Proteopedia. In contrast, [[Proteopedia:News]] lists '''external''' news such as adoptions, blogs, press, meetings, seminars and workshops about Proteopedia.

A major purpose of this page is to make it easier for users to find out about new user-created pages with substantial content. Only user-created pages that have substantial content (at least one paragraph of user-added text with three or more green links), and that are reasonably complete should be listed below. Pages that are started, but not yet completed, should not be listed until they are reasonably complete. Automatically seeded new pages, titled with PDB codes, are not listed here<ref>You can find new entries in the [[PDB]] by going to [http://www.rcsb.org RCSB] and searching by date range.</ref>. Minor updates to existing pages should not be listed.
<div style='float: right; width: 50%;'>
<br><br>
<br><br>
<br><br>
<br><br>
Please add new items at the top. If a linked page is not new, but has been updated with substantial new content, please say so. Each page's ''history'' tab (at the top) shows when it was created and the date of each update.
<br><br>
The left arrow symbol (<-) signifies a page that [[Help:Editing#Redirecting_One_Page_to_Another_Page|redirects]] to another page.
</div>

----
== May, 2010 ==
*[[Rhodopsin]]

== April, 2010 ==
*[[Green Fluorescent Protein]], significant additions have been made to this page.
*[[NADPH Cytochrome P450 Oxidoreductase]]
*[[Proteopedia:Twitter]] - Proteopedia is now on Twitter. '''Follow us at [http://twitter.com/proteopedia Proteopedia on Twitter]'''.
*[[7ahl|The pore forming toxin, α-hemolsyin]]

== March, 2010 ==
*[[Serine Proteases: A Tutorial of Chymotrypsin, Trypsin and Elastase]], examines the structural basis of specificity and a general properties of the catalytic mechanism

== January, 2010 ==
*[[Archaeal Histones]], illustrates the structural features of two histones and a dimer of one of them.
*[[Syn and anti nucleosides]], illustrates the structural differences in the syn and anti configurations of nucleosides.
*[[Ramachandran Plots]], this page is a copy of User:Karl Oberholser/Ramachandran Plots which is a protected page.
*[[3cb4|''Escherichia coli'' LepA, the ribosomal back translocase]]

==December, 2009==
''This month's list is incomplete:''
*[[User:Wayne Decatur/Interactions between Antibiotics and the Ribosome|Interactions between Antibiotics and the Ribosome]]
*[[User:Wayne_Decatur/Haloarcula Large Ribosomal Subunit|Large Ribosomal Subunit of ''Haloarcula marismortui'']]
*[[User:Wayne_Decatur/Haloarcula Large Ribosomal Subunit With Azithromycin|Azithromycin bound to the Large Ribosomal Subunit of Haloarcula]]
*[[Reverse transcriptase]]

==November, 2009==
''This month's list is incomplete:''
*[[1gm5|RecG in complex with a synthetic three-way DNA junction resembling a stalled replication fork]]
*[[3ews|DExD/H-box RNA-dependent ATPase DDX19 in the open]] and [[3g0h|closed]] cleft conformation

==October, 2009==
''This month's list is incomplete:''
*[[Ribosome]], also featured at the [[Main Page]], since its structures won the [[Nobel Prizes for 3D Molecular Structure|Nobel Prize in Chemistry]] this month!
*[[Intrinsically Unfolded Proteins (IUP)]]
*[[Extremophiles]]
*[[Proteopedia:Guidelines for Ethical Writing]]

==July, 2009==
''This month's list is incomplete:''
*[[Influenza hemagglutinin]]
*The 21st and 22nd amino acids were added to [[Amino Acids]]: namely [[Selenocysteine]] and [[Pyrrolysine]].

==March, 2009==
''This month's list is incomplete:''
*[[Mechanosensitive channels: opening and closing]] includes morphs of the ion-conducting channel opening and closing.
*[[High school teachers' resources]]
*[[Richards, Frederic M.]] (1925-2009) including a photo of "Fred's Folly".

==February, 2009==
''This month's list is incomplete:''
*[[Ion channels]] is an attempt to cover a family of proteins and list their available PDB structures.

==January, 2009==
''This month's list is incomplete:''

==December, 2008==
*[[Conservation, Evolutionary]] now includes instructions on how to show a ConSurf result as a scene in Proteopedia, complete with the standard ConSurf color key.
*[[Resolution]] now includes a movie illustrating the relation between the atomic model and the electron density map while resolution ranges from 0.5 to 5.0 Ångstroms.

==November, 2008==
*[[Suppression of RNA Silencing by Viruses|RNA silencing: suppression by viruses]]. Concerns the research awarded the [http://nobelprize.org/nobel_prizes/medicine/laureates/2006/ 2006 Nobel Prize in Physiology or Medicine]. Linked are new pages on specific RNA silencing proteins: [[Plant Viral Protein p19 Suppression of RNA Silencing|Plant viral protein p19]], [[Tomato aspermy virus protein 2b Suppression of RNA Silencing|Tomato aspermy virus protein 2b]], and [[Flock house virus B2 protein Suppression of RNA Silencing|Flock house virus B2 protein]].
*[[Transcription Termination Factor Rho]].
*Mechanosensitive ion channel of large conductance, with open, intermediate, and closed conformations, [[2oar]].
*Crucial role of electrostatic features in halotolerance of carbonic anhydrase, [[1y7w]].
*[[Hydrogen in macromolecular models]]
*[[Molecular modeling and visualization software]], whick links to new pages on [[PyMOL]], [[Jmol]], [[RasMol]], and [[Chime]].

==October, 2008==
*[[Lac repressor]] structure, including a morph of the DNA-binding domain bending the operator DNA.
*Poly(A) Polymerase, [[2q66]]: A new section complementing this month's article in [[Molecule of the Month]].
*[[Structure Gallery Generator]] generates galleries of thumbnail molecular images, linked to Proteopedia, for external websites or within Proteopedia pages.
*Acetylcholinesterase in complex with anti-Alzheimer's drug candidates: Crystal packing mediates enantioselective ligand recognition, [[1zgb]].
*Thermal stability analysis of alcohol dehydrogenase: [[2oui]], [[2nvb]].
*Confirmation of a heterodimer predicted by computational genomic analysis (neither chain could be crystallized alone): [[2g38]].
*Complex Of ''S. griseus'' Proteinase B And Polypeptide Chymotrypsin Inhibitor-1 From Russet Burbank Potato Tubers, [[4sgb]].
*''Structures Saving the Most Lives'' is a new list added to the [[Highest impact structures]] page originally created in February, 2008.
*[[Hydrogen bonds]]
*[[Nobel Prizes for 3D Molecular Structure]]
*[[Morphs]]: Although this page was created in March, 2008, most of its content was added this month.
*[[Proteopedia: Email list]]
*[[Proteopedia:What's New|What's New in Proteopedia?]] (this page).
*Several pages about visualization software: [[FirstGlance in Jmol]], [[Swiss-PDBViewer = DeepView]], and [[Protein Explorer]].

==September, 2008==
*Anticancer Prodrug CPT-11 complexed with ''Torpedo californica'' Acetylcholinesterase [[1u65]]
*[[Avian Influenza Neuraminidase, Tamiflu and Relenza]]
*Insecticidal delta-endotoxin [[Cyt2Ba]] from ''Bacillus thuringiensis''.
*TEM1-β-Lactamase/ β-Lactamase Inhibitor Protein (BLIP), [[2b5r]] and [[1s0w]].
*Acid-beta-glucosidase covalently bound to conduritol B epoxide, [[1y7v]].
*Ribonuclease A, [[1rta]] has a new section complementing this month's article in [[Molecule of the Month]].
*[[DRuMS]], standard color schemes for macromolecules, and color key templates for use in Proteopedia.
*[[User:Tom Gluick/glutamine synthetase|Glutamine Synthetase]], which includes instructions on how to use the Jmol console for advanced scene authoring.

==August, 2008==
*[[HIV-1 protease]]
*[[Pyruvate phosphate dikinase]] with a morph of the catalytic reaction and conformational changes.
*[[Enzyme I of the Phosphoenolpyruvate:Sugar Phosphotransferase System]] with a morph of the catalytic reaction and conformational changes.
*[[Antizyme Inhibitor]]
*Selenocysteine Synthase, [[SelB Recognition]] is a new page complementing this month's article in [[Molecule of the Month]].
*[[Teaching Strategies Using Proteopedia‎]]
*[[User:J._Shaun_Lott/BIOSCI_203|Protein structure lesson plan for BioSci 203]]
*[[Proteopedia: News]]

==July, 2008==
*[[Biotin Protein Ligase]]
*YAGE, A Prophage Protein Belonging To The Dihydrodipicolinic Acid Synthase Family From E. Coli K12, [[2v9d]].
*[[User:Karl_Oberholser/Ramachandran_Plots|Ramachandran Plots]]
*[[Flexibility of aromatic residues in acetylcholinesterase]]
*Horizontal gene transfer ssDNA binding protein from ''Agrobacterium tumefaciens'' [[VirE1/VirE2]]=[[3btp]]
*[[Proteopedia:Page of the Year Competition]]
*[[Student Projects]]

==June 2008==
*Computational design of a Kemp elimination catalyst [[2rkx]].
*[[Recoverin, a calcium-activated myristoyl switch‎]]
*G protein, ras oncogene: [[James_D_Watson/Proteins_Intro]].
*[[Ribulose-1,5-bisphosphate carboxylase/oxygenase]] uses the Kinemage applet.
*[[Acid-beta-glucosidase]]
*[[Rop protein]]

*[[Institute of Clinical Biochemistry]], Oslo, Norway.
*[[Research Groups]] <- [[Institutes]]
*[[Teaching Scenes, Tutorials, and Educators' Pages‎]]

'''About Macromolecular Structure'''
*[[About Macromolecular Structure]] <- [[About Protein Structure]]
*[[Amino Acids]]
*[[Asymmetric Unit]]
*[[Atomic coordinate file]]
*[[Biological Unit]] <- [[Quaternary structure]]
*[[Free R]]
*[[NMR Ensembles of Models‎]]
*[[PDB identification code]]
*[[Quality assessment for molecular models]]
*[[R value]]
*[[Resolution]]
*[[Temperature value]] <- [[Disorder]], [[B value]]
*[[Unit cell]]

==May 2008==
*[[Acetylcholinesterase]]
*[[2ace]] with an overview of the significance of this, the first acetylcholinesterase structure.
*Anti-Alzheimer's drug, Aricept, complexed with acetylcholinesterase [[1eve]].
*Tacrine Binding To Aromatic Residues In The Active-site Gorge Of Acetylcholinesterase, [[1acj]].
*Serum Paraoxonase-1 (PON1) via directed evolution [[1v04]].
*Human acid-beta-glucosidase, [[1ogs]].
*[[Photosystem II]], an undergraduate project.
*[[Ozonolysis]]: cool animation of a chemical reaction!

*[[Help:Copying FirstGlance Scenes into Proteopedia]]

==April 2008==
*Acetylcholinesterase inhibited by nerve agent soman [[1som]].
*Highest resolution acetylcholinesterase so far, [[1ea5]].
*Tetramerization domain of acetylcholinesterase [[1vzj]].
*Locations of mutations in oncogene phosphatidylinositol 3-kinase [[2rd0]], with many of the published figures made interactive in Jmol.
*Escherichia coli GlpG, an integral membrane protein rhomboid protease, unique in cleaving the transmembrane domains of other membrane proteins, [[2ic8]].
*[[Major Histocompatibility Complex Class I]] (no Jmol yet)
*[[Personal favorites]]
*[[Believe It or Not!]]
*[[Help:Protected Pages]]

==March 2008==
*Conformational flexibility in the peripheral site of Torpedo californica acetylecholinesterase revealed by the complex structure with a bifunctional inhibitor, [[2cek]].
*[[Proton Channels]]
*[[Proteopedia:Namespaces]]
*[[Proteopedia:About]]
*[[SGAP]] Streptomyces griseus Aminopeptidase (SGAP) (''no Jmol'')

==February 2008==
*[[Hemoglobin]]
*[[Highest impact structures]] of all time.
*[[Nucleosomes]]
*Scorpion alpha-toxin [[1qlh]].
*[[Peptide]]
*[[Proteopedia:Problems]]
*[[Personal favorites]]

==January 2008==
*[[AChE inhibitors and substrates]]
*[[Dihydrofolate reductase]]

==October-December 2007==
*[[Serine Protease]]
*[[Nqo1]] NADH quinone oxidoreductase (NQO1) in complex with its potent inhibitor dicoumarol.
*[[1xjo]] ''S. griseus'' aminopeptidase.
*[[Glycine]]
*[[Bacterial Intein-Like Domains (BILs)]] (no Jmol, no green links)
*[[Hint auto-proteolytic protein-processing domains]] (no Jmol, no green links)

==See Also==

*[[Proteopedia:News]]
*[[Proteopedia: Email list]]
*[[Special:Newpages|Newest Pages]] appears to list only the current month, and mostly automatically seeded pages.
*[[Special:Recentchanges|Most Recent Changes]]
*[[Topic pages]]

==Notes==
<references />

Rhodopsin

2010-05-02T03:41:21Z

Cinting Lim: New page: {{STRUCTURE_1u19| PDB=1u19 | SCENE=Sandbox_173/Default_rhodopsin_pdb_1u19/1 }} ==Introduction== ===Rhodopsin=== Rhodopsin, a homodimeric protein, is a highly characterized [http://en....

{{STRUCTURE_1u19| PDB=1u19 | SCENE=Sandbox_173/Default_rhodopsin_pdb_1u19/1 }}
==Introduction==
===Rhodopsin===
Rhodopsin, a homodimeric protein, is a highly characterized [http://en.wikipedia.org/wiki/G_protein-coupled_receptor G protein-coupled receptor] found in membranous disks of the outer segments of rod and cone cells, though rhodopsin is more concentrated in rod cells which are sensitive to light but cannot discriminate colors. Rhodopsin is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others<ref name="Article1">PMID:20004206</ref>. Rhodopsin is involved in visual signal transduction and the visual system in classic G protein-coupled receptor mechanisms<ref name="Article12">PMID:11891118</ref>.

===G Protein-Coupled Receptors===
Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signaling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref name="Article20">PMID:15251227</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref name="Article12"/>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref name="Article20"/>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref name="Article10">PMID:11698103</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref name="Article20"/>.

==Structure==
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Structure of Rhodopsin. The generated structures are from Chain A.'/>
===Rhodopsin Architecture===
Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail<ref name="Article12"/>. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane<ref name="Article4">PMID:9199406</ref>. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains<ref name="Article9">PMID:11343925</ref>. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif<ref name="Article9"/>. Near the retinal region, there is a <scene name='Sandbox_173/Beta_4_strand_and_retinal/2'>β4 strand (Serine 186-Cysteine 187-Glycine 188-Isoleucine 189)</scene> within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place and is stabilized by the essential conserved
<scene name='Sandbox_173/Disulfide_bond/4'>disulfide bond between Cysteine 110 and Cysteine 187</scene>. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191<ref name="Article12"/>.

<scene name='Sandbox_173/Water_molecules/1'>Water molecules</scene> are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur<ref name="ReferenceArticle">PMID:15327956</ref>.

There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from <scene name='Sandbox_173/Helix_8/1'>Asparagine 310 to Cysteine 323</scene> and is formed from the C-terminal tail anchoring to the membrane by
<scene name='Sandbox_173/Cys322_and_cys323/1'>Cysteine 322 and Cysteine 323</scene>, which are <scene name='Sandbox_173/Palmitates/3'>palmitoylated</scene>. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding<ref name="Article9"/>, as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions<ref name="Article12"/>.

A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation<ref name="Article10"/>.

The structure of rhodopsin may provide stability to the important Schiff base linkage with the retinal by affecting its hydrolysis, limiting its interactions with solvent, and inhibiting its release when hydrolyzed, thus encouraging rebinding of the Schiff base linkage<ref name="Article3">PMID:14611935</ref>.

<applet load='1u19' size='300' color='black' frame='true' align='right' caption='11-cis Retinylidene Chromophore. The generated structures are from Chain A.'/>

===Retinal Chromophore of Rhodopsin===
Rhodopsin consists of an opsin [http://en.wikipedia.org/wiki/Apoprotein apoprotein] and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref name="Article19">PMID:16051215</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref name="Article12"/>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in <font color='#00FF00'>green</font>) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref name="Article4"/>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref name="Article20"/>.

As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref name="Article2">PMID:16962138</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation<ref name="ReferenceArticle"/>.
Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including the second extracellular loop, which folds into the molecular center<ref name="Article6">PMID:18692154</ref>.

==Function==
===Visual Signal Transduction===
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Residues Involved in Activation of Rhodopsin. The generated structure is from Chain A.'/>
====Photoisomerization of 11-''cis'' Retinal====
The 11-''cis'' retinal (retinylidene) Schiff base functions as an [http://en.wikipedia.org/wiki/Inverse_agonist inverse agonist] and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomerization of rhodopsin, as light energy absorbed from a photon is converted into chemical energy. As a photon is absorbed by the retina, the 11-''cis'' retinylidene ligand is switched into an all-''trans'' retinal configuration<ref name="Article2"/>. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-''cis'' conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form<ref name="Article2"/>.

====Adjustment and Thermal Relaxation of the Protein====
Upon activation, movement and slight adjustment of helices are observed, with the inner faces of Helix 2, 3, 6 and 7 becoming more exposed<ref name="Article10"/>. As Helices 3 and 6 move outward, the binding site for transducin is more accessible as there is opening between cytoplasmic loops<ref name="Article19"/>.
Following activation, a slower thermal relaxation process occurs. This involves conformational changes in the retinal and opsin to result in fully active Metarhodopsin II<ref name="Article6"/>.

====Formation of the Metarhodopsin II State====
Rhodopsin forms to Metarhodopsin II, the intermediate signaling state where interaction occurs with the G protein. This millisecond process is accompanied by movement in the helices, uptake of protons in the cytoplasm, and the breakage of the salt bridge between Glutamine 113 and the protonated Schiff base. The Schiff base deprotonates and the proton is transferred to the Glutamine 113 counterion, destabilizing the ground state <ref name="Article9"/>. As well, this Metarhodopsin II formation may be dependent on the protonation too of the conserved <scene name='Sandbox_173/Glu134_and_arg135/1'>Glutamine 134 that forms a salt bridge with Arginine 135</scene>, thus destabilizing the constraint on Arginine 135<ref name="Article9"/>.

There is positive enthalpy associated with the formation of Metarhodopsin II. This formation of the active state, also linked with the increase in entropy, is suggested to release the constraints in the helices and expose the cytoplasmic binding sites<ref name="Article9"/>. An important part of this process includes the 9-methyl group of retinal, which is suggested to provide a scaffold for proton transfers essential for the formation of the active state<ref name="Article9"/>.

====Signaling Cascade and Polarization of the Cell Membrane====
[[image:RhodopsinTransducinComplex.jpg|thumb|left|Rhodopsin interaction with transducin.]]
The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasmic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref name="Article6"/>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref name="Textbook">Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.</ref>.
The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity. The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP<ref name="Textbook"/>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref name="Article6"/>.

===Visual Signal Termination===
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Phosphorylation of Rhodospin. The generated structure is from Chain A.'/>
====Recovery of the Pre-stimulus State====
In the event of a decrease in light intensity, GTP is hydrolyzed and the α-subunit of transducin reassociates with the βγ subunits, releasing the inhibitory subunit of phosphodiesterase. This subunit reassociates with phosphodiesterase and inhibits its activity<ref name="Textbook"/>.
The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by [http://en.wikipedia.org/wiki/Guanylate_cyclase guanylyl cyclase], activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref name="Textbook"/>.

====Phosphorylation and Deactivation of Rhodopsin====
[http://en.wikipedia.org/wiki/Rhodopsin_kinase Rhodopsin kinase] phosphorylates rhodopsin and [http://en.wikipedia.org/wiki/Arrestin arrestin] binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref name="Article3"/>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref name="Article7">PMID:9667002</ref>, and these residues form an arrangement in rhodopsin that do not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref name="Article9"/>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref name="Article19"/>.

Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation<ref name="Article9"/>.

==Opsin==
<applet load='3cap' size='300' color='black' frame='true' align='right' caption='Structure of Opsin†. The generated structure is from Chain A.'/>
===Topology Overview===
The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref name="ArticleOpsin2">PMID:18563085</ref>. Also, in contrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref name="ArticleOpsin2"/>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref name="ArticleOpsin2"/>.

===Activity===
The ability of opsin to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref name="ArticleOpsin1">PMID:9628807</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref name="ArticleOpsin1"/>.

===Colour Vision===
Opsins are also photoreceptor proteins and are concentrated in cone cells, cells that are less sensitive to light but can discriminate colours. Opsins are slightly different light receptors than rhodopsin in that they can detect light from different spectrums and distinguish between their wavelengths. The ability to differentiate between colours is related to the three types of cone cells, each using one of the three related opsin photoreceptors<ref name="Textbook"/>.

† PDB structure used in this section: [[3cap]]

==References==

[[Category: G protein-coupled receptor]]
[[Category: Membrane protein]]
[[Category: Photoreceptor]]
[[Category: Retinal protein]]

<references/>

2010-03-30T02:35:50Z

Cinting Lim:

{{STRUCTURE_1u19| PDB=1u19 | SCENE=Sandbox_173/Default_rhodopsin_pdb_1u19/1 }}
==Introduction==
===Rhodopsin===
Rhodopsin, a homodimeric protein, is a highly characterized [http://en.wikipedia.org/wiki/G_protein-coupled_receptor G protein-coupled receptor] found in membranous disks of the outer segments of rod and cone cells, though rhodopsin is more concentrated in rod cells. It is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others<ref>Article 1</ref>. Rhodopsin is involved in visual signal transduction and the visual system in classic G protein-coupled receptor mechanisms<ref>Article 12</ref>.

===G Protein-Coupled Receptors===
Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref>Article 20</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref>Article 12</ref>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref>Article 20</ref>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case transducin, which interacts with the cytoplasmic loops of the receptor<ref>Article 10</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref>Article 20</ref>.

==Structure==
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Structure of Rhodopsin. The generated structures are from Chain A.'/>
===Rhodopsin Architecture===
Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail<ref>Article 12</ref>. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane<ref>Article 4</ref>. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains<ref>Article 9</ref>. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif<ref>Article 9</ref>. Near the retinal region, there is a <scene name='Sandbox_173/Beta_4_strand_and_retinal/2'>β4 strand (Serine 186-Cysteine 187-Glycine 188-Isoleucine 189)</scene> within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place and is stabilized by the essential conserved
<scene name='Sandbox_173/Disulfide_bond/4'>disulfide bond between Cysteine 110 and Cysteine 187</scene>. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191<ref>Article 12</ref>.

<scene name='Sandbox_173/Water_molecules/1'>Water molecules</scene> are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur<ref>Original article</ref>.

There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from <scene name='Sandbox_173/Helix_8/1'>Asparagine 310 to Cysteine 323</scene> and is formed from the C-terminal tail anchoring to the membrane by
<scene name='Sandbox_173/Cys322_and_cys323/1'>Cysteine 322 and Cysteine 323</scene>, which are <scene name='Sandbox_173/Palmitates/3'>palmitoylated</scene>. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding<ref>Article 9</ref>, as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions<ref>Article 12</ref>.

A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation<ref>Article 10</ref>.

The structure of rhodopsin may provide stability to the important Schiff base linkage with the retinal by affecting its hydrolysis, limiting its interactions with solvent, and inhibiting its release when hydrolyzed, thus encouraging rebinding of the Schiff base linkage<ref>Article 3</ref>.

<applet load='1u19' size='300' color='black' frame='true' align='right' caption='11-cis Retinylidene Chromophore. The generated structures are from Chain A.'/>

===Retinal Chromophore of Rhodospin===
Rhodopsin consists of an opsin apoprotein and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref>Article 12</ref>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in <font color='#00FF00'>green</font>) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref>Article 4</ref>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>.

As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref>Article 2</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>.
Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including Extracellular Helix 2, which folds into the molecular center<ref>Article 6</ref>.

==Function==
===Visual Signal Transduction===
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Residues Involved in Activation of Rhodopsin. The generated structure is from Chain A.'/>
====Photoisomeration of 11-''cis'' Retinal====
The 11-''cis'' retinal (retinylidene) Schiff base functions as an [http://en.wikipedia.org/wiki/Inverse_agonist inverse agonist] and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomeration of rhodopsin, as light energy absorbed from a photon is converted into chemical energy, As a photon is absorbed by the retina, the 11-''cis'' retinylidene ligand is switched into an all-''trans'' retinal configuration<ref>Article 2</ref>. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-''cis'' conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form<ref>Article 2</ref>.

====Adjustment and Thermal Relaxation of the Protein====
Upon activation, movement and slight adjustment of helices are observed, with the inner faces of Helix 2, 3, 6 and 7 becoming more exposed<ref>Article 10</ref>. As Helices 3 and 6 move outward, the binding site for transducin is more accessible as there is opening between cytoplasmic loops<ref>Article 19</ref>.
Following activation, a slower thermal relaxation process occurs. This involves conformational changes in the retinal and opsin to result in fully active Metarhodopsin II<ref>Article 6</ref>.

====Formation of the Metarhodopsin II State====
Rhodopsin forms to Metarhodopsin II, the intermediate signaling state where interaction occurs with the G protein. This millisecond process is accompanied by movement in the helices, uptake of protons in the cytoplasm, and the breakage of the salt bridge between Glutamine 113 and the protonated Schiff base. The Schiff base deprotonates and the proton is transferred to the Glutamine 113 counterion, destabilizing the ground state <ref>Article 9</ref>. As well, this Metarhodopsin II formation may be dependent on the protonation too of the conserved <scene name='Sandbox_173/Glu134_and_arg135/1'>Glutamine 134 that forms a salt bridge with Arginine 135</scene>, thus destabilizing the constraint on Arginine 135<ref>Article 9</ref>.

There is positive enthalpy associated with the formation of Metarhodopsin II. This formation of the active state, also linked with the increase in entropy, is suggested to release the constraints in the helices and expose the cytoplasmic binding sites<ref>Article 9</ref>. An important part of this process includes the 9-methyl group of retinal, which is suggested to provide a scaffold for proton transfers essential for the formation of the active state<ref>Article 9</ref>.

<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Phosphorylation of Rhodospin. The generated structure is from Chain A.'/>
====Signalling Cascade and Polarization of the Cell Membrane====
The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates cGMP-specific phosphodiesterase by binding and removing its inhibitory subunit<ref>Textbook</ref>.
The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity. The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP <ref>Textbook</ref>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref>Article 6</ref>.

===Visual Signal Termination===
====Recovery of the Pre-stimulus State====
In the event of a decrease in light intensity, GTP is hydrolyzed and the α-subunit of transducin reassociates with the βγ subunits, releasing the inhibitory subunit of phosphodiesterase. This subunit reassociates with phosphodiesterase and inhibits its activity<ref>Textbook</ref>.
The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by guanylyl cyclase, activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref>Textbook</ref>.

====Phosphorylation and Deactivation of Rhodopsin====
Rhodopsin kinase phosphorylates rhodopsin and arrestin binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref>Article 3</ref>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref>Article 7</ref>, and these residues form an arrangement in rhodopsin that does not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref>Article 9</ref>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref>Article 19</ref>.

Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation<ref>Article 9</ref>.

==Opsin==
<applet load='3cap' size='300' color='black' frame='true' align='right' caption='Structure of Opsin†. The generated structure is from Chain A.'/>
===Topology Overview===
The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref>Article Opsin 2</ref>. Also, in constrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref>Article Opsin 2</ref>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref>Article Opsin 2</ref>.

===Activity===
Opsin is the [http://en.wikipedia.org/wiki/Apoprotein apoprotein] component of rhodopsin. Its ability to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref>Article Opsin 1</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref>Article Opsin 1</ref>.

===Colour Vision===
Opsins are also photoreceptor proteins and are concentrated in cone cells, cells that are less sensitive to light but can discriminate colours, unlike rod cells. Opsins are slightly different light receptors than rhodopsin in that they can detect light from different spectrums and distinguish between their wavelengths. The ability to differentiate between colours is related to the three types of cone cells, each using one of the three related opsin photoreceptors<ref>Textbook</ref>.

† PDB structure used in this section: [[3cap]]

==References==
<ref group="xtra">PMID:15327956</ref><references group="xtra"/>
[[Category: Bos taurus]]
[[Category: Bondar, A N.]]
[[Category: Buss, V.]]
[[Category: Elstner, M.]]
[[Category: Entel, P.]]
[[Category: Okada, T.]]
[[Category: Sugihara, M.]]
[[Category: G protein-coupled receptor]]
[[Category: Membrane protein]]
[[Category: Photoreceptor]]
[[Category: Retinal protein]]

<references/>
<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr>

Sandbox 173

2010-03-29T21:19:35Z

Cinting Lim:

{{STRUCTURE_1u19| PDB=1u19 | SCENE=Sandbox_173/Default_rhodopsin_pdb_1u19/1 }}
==Introduction==
===Rhodopsin===
Rhodopsin, a homodimeric protein, is a highly characterized G protein-coupled receptor found in membranous disks of the outer segments of rod and cone cells, though rhodopsin is more concentrated in rod cells. It is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others<ref>Article 1</ref>. Rhodopsin is involved in visual signal transduction and the visual system in classic G protein-coupled receptor mechanisms<ref>Article 12</ref>.

===G Protein-Coupled Receptors===
Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref>Article 20</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref>Article 12</ref>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref>Article 20</ref>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case transducin, which interacts with the cytoplasmic loops of the receptor<ref>Article 10</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref>Article 20</ref>.

==Structure==
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Structure of Rhodopsin. The generated structures are from Chain A.'/>
===Rhodopsin Architecture===
Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail<ref>Article 12</ref>. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane<ref>Article 4</ref>. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains<ref>Article 9</ref>. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif<ref>Article 9</ref>. Near the retinal region, there is a <scene name='Sandbox_173/Beta_4_strand_and_retinal/2'>β4 strand (Serine 186-Cysteine 187-Glycine 188-Isoleucine 189)</scene> within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place and is stabilized by the essential conserved
<scene name='Sandbox_173/Disulfide_bond/4'>disulfide bond between Cysteine 110 and Cysteine 187</scene>. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191<ref>Article 12</ref>.

<scene name='Sandbox_173/Water_molecules/1'>Water molecules</scene> are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur<ref>Original article</ref>.

There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from <scene name='Sandbox_173/Helix_8/1'>Asparagine 310 to Cysteine 323</scene> and is formed from the C-terminal tail anchoring to the membrane by
<scene name='Sandbox_173/Cys322_and_cys323/1'>Cysteine 322 and Cysteine 323</scene>, which are <scene name='Sandbox_173/Palmitates/3'>palmitoylated</scene>. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding<ref>Article 9</ref>, as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions<ref>Article 12</ref>.

A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation<ref>Article 10</ref>.

The structure of rhodopsin may provide stability to the important Schiff base linkage with the retinal by affecting its hydrolysis, limiting its interactions with solvent, and inhibiting its release when hydrolyzed, thus encouraging rebinding of the Schiff base linkage<ref>Article 3</ref>.

<applet load='1u19' size='300' color='black' frame='true' align='right' caption='11-cis Retinylidene Chromophore. The generated structures are from Chain A.'/>

===Retinal Chromophore of Rhodospin===
Rhodopsin consists of an opsin apoprotein and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref>Article 12</ref>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in <font color='#00FF00'>green</font>) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref>Article 4</ref>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>.

As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref>Article 2</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>.
Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including Extracellular Helix 2, which folds into the molecular center<ref>Article 6</ref>.

==Function==
===Visual Signal Transduction===
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Residues Involved in Activation of Rhodopsin. The generated structure is from Chain A.'/>
====Photoisomeration of 11-''cis'' Retinal====
The 11-''cis'' retinal (retinylidene) Schiff base functions as an inverse agonist and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomeration of rhodopsin, as light energy absorbed from a photon is converted into chemical energy, As a photon is absorbed by the retina, the 11-''cis'' retinylidene ligand is switched into an all-''trans'' retinal configuration<ref>Article 2</ref>. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-''cis'' conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form<ref>Article 2</ref>.

====Adjustment and Thermal Relaxation of the Protein====
Upon activation, movement and slight adjustment of helices are observed, with the inner faces of Helix 2, 3, 6 and 7 becoming more exposed<ref>Article 10</ref>. As Helices 3 and 6 move outward, the binding site for transducin is more accessible as there is opening between cytoplasmic loops<ref>Article 19</ref>.
Following activation, a slower thermal relaxation process occurs. This involves conformational changes in the retinal and opsin to result in fully active Metarhodopsin II<ref>Article 6</ref>.

====Formation of the Metarhodopsin II State====
Rhodopsin forms to Metarhodopsin II, the intermediate signaling state where interaction occurs with the G protein. This millisecond process is accompanied by movement in the helices, uptake of protons in the cytoplasm, and the breakage of the salt bridge between Glutamine 113 and the protonated Schiff base. The Schiff base deprotonates and the proton is transferred to the Glutamine 113 counterion, destabilizing the ground state <ref>Article 9</ref>. As well, this Metarhodopsin II formation may be dependent on the protonation too of the conserved <scene name='Sandbox_173/Glu134_and_arg135/1'>Glutamine 134 that forms a salt bridge with Arginine 135</scene>, thus destabilizing the constraint on Arginine 135<ref>Article 9</ref>.

There is positive enthalpy associated with the formation of Metarhodopsin II. This formation of the active state, also linked with the increase in entropy, is suggested to release the constraints in the helices and expose the cytoplasmic binding sites<ref>Article 9</ref>. An important part of this process includes the 9-methyl group of retinal, which is suggested to provide a scaffold for proton transfers essential for the formation of the active state<ref>Article 9</ref>.

<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Phosphorylation of Rhodospin. The generated structure is from Chain A.'/>
====Signalling Cascade and Polarization of the Cell Membrane====
The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref>Article 6</ref>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates cGMP-specific phosphodiesterase by binding and removing its inhibitory subunit<ref>Textbook</ref>.
The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity. The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP <ref>Textbook</ref>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref>Article 6</ref>.

===Visual Signal Termination===
====Recovery of the Pre-stimulus State====
In the event of a decrease in light intensity, GTP is hydrolyzed and the α-subunit of transducin reassociates with the βγ subunits, releasing the inhibitory subunit of phosphodiesterase. This subunit reassociates with phosphodiesterase and inhibits its activity<ref>Textbook</ref>.
The concentration of cGMP is returned to the “dark” state by the conversion of GTP to cGMP by guanylyl cyclase, activated through the efflux of calcium ions through the sodium/calcium ion exchanger. The reduction in the concentration of calcium ions also inhibits phosphodiesterase activity. Both actions reopen the cation channels and restore the system to pre-stimulus state<ref>Textbook</ref>.

====Phosphorylation and Deactivation of Rhodopsin====
Rhodopsin kinase phosphorylates rhodopsin and arrestin binds to the phosphorylated domain of rhodopsin, preventing further signal transduction from Metarhodopsin II of activated rhodopsin and transducin<ref>Article 3</ref>. It phosphorylates both Metarhodopsin II and cone opsins. The majority of the phosphorylation sites are in the cytoplasmic C-terminal region of rhodopsin with seven hydroxy-amino acids. The most favoured amino acids are <scene name='Sandbox_173/Phosphorylated_sites/1'>Serine 338, Serine 343, Serine 334, Threonine 335 and Threonine 336</scene><ref>Article 7</ref>, and these residues form an arrangement in rhodopsin that does not appear to be exposed to the solvent. Interactions with the C-terminal tail and a portion of the Cytoplasmic loop 3 appear to be broken for the phosphorylation of the hydroxyl groups<ref>Article 9</ref>. For the next cycle of activation of rhodopsin, rhodopsin has to be dephosphorylated, and have the all-''trans'' retinal replaced with the 11-''cis'' retinal<ref>Article 19</ref>.

Altogether, the different states of rhodopsin which include the short-lived, photo-rhodopsin, batho-rhodopsin, and lumi-rhodopsin, and longer-lived meta-rhodopsins give information about the structural status of the molecule during activation<ref>Article 9</ref>.

==Opsin==
<applet load='3cap' size='300' color='black' frame='true' align='right' caption='Structure of Opsin†. The generated structure is from Chain A.'/>
===Topology Overview===
The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref>Article Opsin 2</ref>. Also, in constrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref>Article Opsin 2</ref>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref>Article Opsin 2</ref>.

===Activity===
Opsin is the apoprotein component of rhodopsin. Its ability to activate transducin is modulated by both 11-''cis'' retinal and the all-''trans'' retinal; the 11-''cis'' retinal reduces its activity while the all-''trans'' retinal enhances it through non-covalent interactions <ref>Article Opsin 1</ref>. This may give insight on the ability of all-''trans'' retinal, in combination with opsin, to alter the photoreceptor sensitivities<ref>Article Opsin 1</ref>.

===Colour Vision===
Opsins are also photoreceptor proteins and are concentrated in cone cells, cells that are less sensitive to light but can discriminate colours, unlike rod cells. Opsins are slightly different light receptors than rhodopsin in that they can detect light from different spectrums and distinguish between their wavelengths. The ability to differentiate between colours is related to the three types of cone cells, each using one of the three related opsin photoreceptors<ref>Textbook</ref>.

† PDB structure used in this section: [[3cap]]

==References==
<ref group="xtra">PMID:15327956</ref><references group="xtra"/>
[[Category: Bos taurus]]
[[Category: Bondar, A N.]]
[[Category: Buss, V.]]
[[Category: Elstner, M.]]
[[Category: Entel, P.]]
[[Category: Okada, T.]]
[[Category: Sugihara, M.]]
[[Category: G protein-coupled receptor]]
[[Category: Membrane protein]]
[[Category: Photoreceptor]]
[[Category: Retinal protein]]

<references/>
<table style="background-color:#ffffc0" cellpadding="8" width="95%" border="0"><tr><td>Please do NOT make changes to this Sandbox until after April 23, 2010. Sandboxes 151-200 are reserved until then for use by the Chemistry 307 class at UNBC taught by Prof. [[User:Andrea Gorrell|Andrea Gorrell]].</td></tr>