Sandbox Reserved 1165: Difference between revisions

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==How These Structures Lead to Function==

Structurally, the 7TM and its signature seven helical structure is involved in [https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Signaling_inside_the_Cell signaling] via [https://en.wikibooks.org/wiki/Structural_Biochemistry/Energy_coupling_in_chemical_reactions coupling] to [https://en.wikipedia.org/wiki/Heterotrimeric_G_protein heterotrimeric G proteins] that activate [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase] to increase the levels of intracellular [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate cyclic AMP]. Additionally, this coupling increases levels of [https://en.wikipedia.org/wiki/Inositol_phosphate IP3] and intracellular [https://en.wikipedia.org/wiki/Calcium calcium] levels. <ref name="Tips">PMID: 23863937</ref> The wider and deeper ligand-binding pocket of class B GPCRs allows for a vast array of molecules to be bound that in turn allow for numerous functions activated by peptide [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors]. <ref name="Ligands">PMID: 21542831</ref> The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the class B G protein-coupled receptor, which has an open and closed [https://en.wikipedia.org/wiki/Conformation conformation] of the GCGR. When glucagon binds to GCGR, the open conformation of GCGR is stabilized. The [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand has been identified, and the N-terminus of glucagon is known to bind partly with the ECD while the rest of glucagon binds deep into the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene>. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus of the class B 7TM have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions], which can be seen in the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon (Figure 2). <ref name="Sequence">PMID: 11946536</ref>

Structurally, the 7TM and its signature seven helical structure is involved in [https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Signaling_inside_the_Cell signaling] via [https://en.wikibooks.org/wiki/Structural_Biochemistry/Energy_coupling_in_chemical_reactions coupling] to [https://en.wikipedia.org/wiki/Heterotrimeric_G_protein heterotrimeric G proteins] that activate [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase] to increase the levels of intracellular [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate cyclic AMP]. Additionally, this coupling increases levels of [https://en.wikipedia.org/wiki/Inositol_phosphate IP3] and intracellular [https://en.wikipedia.org/wiki/Calcium calcium] levels. <ref name="Tips">PMID: 23863937</ref> The wider and deeper ligand-binding pocket of class B GPCRs allows for a vast array of molecules to be bound that in turn allow for numerous functions activated by peptide [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors]. <ref name="Ligands">PMID: 21542831</ref> The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the class B G protein-coupled receptor, which has an open and closed [https://en.wikipedia.org/wiki/Conformation conformation] of the GCGR. When glucagon binds to GCGR, the open conformation of GCGR is stabilized.

[[Image:Screen_Shot_2016-03-22_at_5.28.03_PM.png|(|):|425 px|center|thumb|'''Figure 4: Binding Pocket Residues:''' Residues with side chains of carbon(utilizing the [https://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic effect]) are shown in green and side chains containing oxygen ([https://en.wikipedia.org/wiki/Hydrophile hydrophilic]) are shown in red. The properties of hydrophobicity and hydrophilicity of the residues create the [https://en.wikipedia.org/wiki/Ligand_%28biochemistry%29#Receptor.2Fligand_binding_affinity binding affinity] of glucagon.]]

The [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand has been identified, and the N-terminus of glucagon is known to bind partly with the ECD while the rest of glucagon binds deep into the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene>. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus of the class B 7TM have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions], which can be seen in the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon (Figure 2). <ref name="Sequence">PMID: 11946536</ref>

[[Image:Aminoacidsequenceglucagon.png|(|):|425 px|center|thumb|'''Figure 2: Amino Acid Sequence of Glucagon''']]

There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the binding pocket of the 7TM (Figure 4). <ref name="Ligands">PMID: 21542831</ref> There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. <ref name="Ligands">PMID: 21542831</ref> This includes the [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between Cys 294 and Cys 224 that was mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity (Figure 3). <ref name="Ligands">PMID: 21542831</ref> Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon. <ref name="Tips">PMID: 23863937</ref>

Many of the [https://en.wikipedia.org/wiki/Residue_(chemistry) residues] in the binding pocket that are in direct contact with the glucagon molecule are [https://en.wikipedia.org/wiki/Ion charged] or are [https://en.wikipedia.org/wiki/Chemical_polarity polar].

[[Image:Screen Shot 2016-03-29 at 3.24.43 PM.png|(|):|400 px|right|thumb|'''Figure 3: Salt Bridge'''. The salt bridge is located on the intracellular side at the bottom of the protein, in relation to the orientation it holds within the cell membrane. It is made between residues Glu 406, Arg 173, and Arg 346, as labeled in the figure.]]

There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the binding pocket of the 7TM (Figure 4). <ref name="Ligands">PMID: 21542831</ref> There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [~~http~~:~~//www~~.~~chemicool~~.~~com/definition/affinity~~.~~html affinity]. <ref name="Ligands">PMID~~: ~~21542831</ref> This includes the [https~~:~~//en~~.~~wikipedia.org/wiki/Disulfide disulfide bond]~~ between ~~Cys 294~~ and ~~Cys 224 that was mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the~~ [https://en.wikipedia.org/wiki/~~Salt_bridge_%28protein_and_supramolecular%29~~ salt ~~bridges] between~~ Glu 406, Arg 173, and Arg ~~346, also mentioned earlier, hold the conformation together for higher affinity (Figure 3)~~. ~~<ref name="Ligands">PMID: 21542831</ref> Finally, alpha helical structure of the stalk~~ is ~~imperative to~~ the ~~affinity and binding~~ of the ~~glucagon~~. ~~<ref name="Tips">PMID: 23863937</ref>~~

[[Image:Screen Shot 2016-03-29 at 3.24.43 PM.png|(|):|400 px|right|thumb|'''Figure 3: Salt Bridge'''. The non-covalent interactions between residues Glu 406, Arg 173, and Arg 346 form a [https://en.wikipedia.org/wiki/Denticity tridentate] salt bridge. The Glu 406 acts as the central residue in the tridentate salt bridge; Arg 173 and Arg 436 both interact with Glu 406. The salt bridge is located on the intracellular side of the transmembrane helices.]]

[[Image:Screen_Shot_2016-03-22_at_5.28.03_PM.png|(|):|425 px|center|thumb|'''Figure 4: Binding Pocket Residues:''' Residues with side chains of carbon(utilizing the [https://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic effect]) are shown in green and side chains containing oxygen ([https://en.wikipedia.org/wiki/Hydrophile hydrophilic]) are shown in red. The properties of hydrophobicity and hydrophilicity of the residues create the [https://en.wikipedia.org/wiki/Ligand_%28biochemistry%29#Receptor.2Fligand_binding_affinity binding affinity] of glucagon.]]

=Glucagon Signaling Pathway=

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@@ Line 16: / Line 16: @@
 ==How These Structures Lead to Function==
-Structurally, the 7TM and its signature seven helical structure is involved in [https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Signaling_inside_the_Cell signaling] via [https://en.wikibooks.org/wiki/Structural_Biochemistry/Energy_coupling_in_chemical_reactions coupling] to [https://en.wikipedia.org/wiki/Heterotrimeric_G_protein heterotrimeric G proteins] that activate [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase] to increase the levels of intracellular [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate cyclic AMP]. Additionally, this coupling increases levels of [https://en.wikipedia.org/wiki/Inositol_phosphate IP3] and intracellular [https://en.wikipedia.org/wiki/Calcium calcium] levels. <ref name="Tips">PMID: 23863937</ref> The wider and deeper ligand-binding pocket of class B GPCRs allows for a vast array of molecules to be bound that in turn allow for numerous functions activated by peptide [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors]. <ref name="Ligands">PMID: 21542831</ref> The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the class B G protein-coupled receptor, which has an open and closed [https://en.wikipedia.org/wiki/Conformation conformation] of the GCGR. When glucagon binds to GCGR, the open conformation of GCGR is stabilized. The [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand has been identified, and the N-terminus of glucagon is known to bind partly with the ECD while the rest of glucagon binds deep into the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene>. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus of the class B 7TM have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions], which can be seen in the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon (Figure 2). <ref name="Sequence">PMID: 11946536</ref>
+Structurally, the 7TM and its signature seven helical structure is involved in [https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Signaling_inside_the_Cell signaling] via [https://en.wikibooks.org/wiki/Structural_Biochemistry/Energy_coupling_in_chemical_reactions coupling] to [https://en.wikipedia.org/wiki/Heterotrimeric_G_protein heterotrimeric G proteins] that activate [https://en.wikipedia.org/wiki/Adenylyl_cyclase adenylate cyclase] to increase the levels of intracellular [https://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphate cyclic AMP]. Additionally, this coupling increases levels of [https://en.wikipedia.org/wiki/Inositol_phosphate IP3] and intracellular [https://en.wikipedia.org/wiki/Calcium calcium] levels. <ref name="Tips">PMID: 23863937</ref> The wider and deeper ligand-binding pocket of class B GPCRs allows for a vast array of molecules to be bound that in turn allow for numerous functions activated by peptide [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors]. <ref name="Ligands">PMID: 21542831</ref> The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the class B G protein-coupled receptor, which has an open and closed [https://en.wikipedia.org/wiki/Conformation conformation] of the GCGR. When glucagon binds to GCGR, the open conformation of GCGR is stabilized.
+[[Image:Screen_Shot_2016-03-22_at_5.28.03_PM.png|(|):|425 px|center|thumb|'''Figure 4: Binding Pocket Residues:''' Residues with side chains of carbon(utilizing the [https://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic effect]) are shown in green and side chains containing oxygen ([https://en.wikipedia.org/wiki/Hydrophile hydrophilic]) are shown in red. The properties of hydrophobicity and hydrophilicity of the residues create the [https://en.wikipedia.org/wiki/Ligand_%28biochemistry%29#Receptor.2Fligand_binding_affinity binding affinity] of glucagon.]]
+The [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand has been identified, and the N-terminus of glucagon is known to bind partly with the ECD while the rest of glucagon binds deep into the <scene name='72/721535/Binding_pocket_orange/1'>binding pocket</scene>. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus of the class B 7TM have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions], which can be seen in the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon (Figure 2). <ref name="Sequence">PMID: 11946536</ref>
 [[Image:Aminoacidsequenceglucagon.png|(|):|425 px|center|thumb|'''Figure 2: Amino Acid Sequence of Glucagon''']]
+There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the binding pocket of the 7TM (Figure 4). <ref name="Ligands">PMID: 21542831</ref> There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. <ref name="Ligands">PMID: 21542831</ref> This includes the [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between Cys 294 and Cys 224 that was mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity (Figure 3). <ref name="Ligands">PMID: 21542831</ref> Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon. <ref name="Tips">PMID: 23863937</ref>
 Many of the [https://en.wikipedia.org/wiki/Residue_(chemistry) residues] in the binding pocket that are in direct contact with the glucagon molecule are [https://en.wikipedia.org/wiki/Ion charged] or are [https://en.wikipedia.org/wiki/Chemical_polarity polar].
-[[Image:Screen Shot 2016-03-29 at 3.24.43 PM.png|(|):|400 px|right|thumb|'''Figure 3: Salt Bridge'''. The salt bridge is located on the intracellular side at the bottom of the protein, in relation to the orientation it holds within the cell membrane. It is made between residues Glu 406, Arg 173, and Arg 346, as labeled in the figure.]]
-There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the binding pocket of the 7TM (Figure 4). <ref name="Ligands">PMID: 21542831</ref> There are specific amino acid interactions that hold the helices of the 7TM in the closed conformation that maximizes [http://www.chemicool.com/definition/affinity.html affinity]. <ref name="Ligands">PMID: 21542831</ref> This includes the [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between Cys 294 and Cys 224 that was mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the [https://en.wikipedia.org/wiki/Salt_bridge_%28protein_and_supramolecular%29 salt bridges] between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity (Figure 3). <ref name="Ligands">PMID: 21542831</ref> Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon. <ref name="Tips">PMID: 23863937</ref>
+[[Image:Screen Shot 2016-03-29 at 3.24.43 PM.png|(|):|400 px|right|thumb|'''Figure 3: Salt Bridge'''.  The non-covalent interactions between residues Glu 406, Arg 173, and Arg 346 form a [https://en.wikipedia.org/wiki/Denticity tridentate] salt bridge. The Glu 406 acts as the central residue in the tridentate salt bridge; Arg 173 and Arg 436 both interact with Glu 406. The salt bridge is located on the intracellular side of the transmembrane helices.]]
-[[Image:Screen_Shot_2016-03-22_at_5.28.03_PM.png|(|):|425 px|center|thumb|'''Figure 4: Binding Pocket Residues:''' Residues with side chains of carbon(utilizing the [https://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic effect]) are shown in green and side chains containing oxygen ([https://en.wikipedia.org/wiki/Hydrophile hydrophilic]) are shown in red. The properties of hydrophobicity and hydrophilicity of the residues create the [https://en.wikipedia.org/wiki/Ligand_%28biochemistry%29#Receptor.2Fligand_binding_affinity binding affinity] of glucagon.]]
 =Glucagon Signaling Pathway=