Sandbox Reserved 1165: Difference between revisions

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==How These Structures Lead to Function==

Structurally, the [https://en.wikipedia.org/wiki/N-terminus N-terminal] extracellular domain (ECD) and the 7TM comprise the signature seven helical structure that 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 [https://en.wikipedia.org/wiki/Inositol_phosphate inositol phosphate] 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 [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors] to be bound that allow for numerous functions activated by peptide receptors <ref name="Ligands">PMID: 21542831</ref>. The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the protein, 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. There is no clear [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand, but they do know the N-terminus of glucagon binds deep into the binding pocket. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions] involved. Here is the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon <ref name="Sequence">PMID: 11946536</ref>.

Structurally, the [https://en.wikipedia.org/wiki/N-terminus N-terminal] <scene name='72/721535/Ecd/2'>extracellular domain (ECD)</scene> and the 7TM comprise the signature seven helical structure that 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 [https://en.wikipedia.org/wiki/Inositol_phosphate inositol phosphate] 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 [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors] to be bound that allow for numerous functions activated by peptide receptors <ref name="Ligands">PMID: 21542831</ref>. The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the protein, 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. There is no clear [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand, but they do know the N-terminus of glucagon binds deep into the <scene name='72/721535/Binding_pocket_plain/1'>binding pocket</scene>. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions] involved. Here is the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon <ref name="Sequence">PMID: 11946536</ref>.

Line 23:

Many of the [https://en.wikipedia.org/wiki/Residue_(chemistry) residues] 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].

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 <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]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the salt bridges between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity. Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.

There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the <scene name='72/721535/Binding_pocket_plain/1'>binding pocket</scene> of the 7TM <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]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> 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. Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.

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@@ Line 16: / Line 16: @@
 ==How These Structures Lead to Function==
-Structurally, the [https://en.wikipedia.org/wiki/N-terminus N-terminal] extracellular domain (ECD) and the 7TM comprise the signature seven helical structure that 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 [https://en.wikipedia.org/wiki/Inositol_phosphate inositol phosphate] 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 [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors] to be bound that allow for numerous functions activated by peptide receptors <ref name="Ligands">PMID: 21542831</ref>. The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the protein, 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. There is no clear [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand, but they do know the N-terminus of glucagon binds deep into the binding pocket. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions] involved. Here is the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon <ref name="Sequence">PMID: 11946536</ref>.
+Structurally, the [https://en.wikipedia.org/wiki/N-terminus N-terminal] <scene name='72/721535/Ecd/2'>extracellular domain (ECD)</scene> and the 7TM comprise the signature seven helical structure that 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 [https://en.wikipedia.org/wiki/Inositol_phosphate inositol phosphate] 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 [https://en.wikipedia.org/wiki/Receptor_(biochemistry) receptors] to be bound that allow for numerous functions activated by peptide receptors <ref name="Ligands">PMID: 21542831</ref>. The conformation and orientation of the 7TM and the ECD regions dictate the functionality of the protein, 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. There is no clear [https://en.wikipedia.org/wiki/Active_site binding site] location of the hormone peptide ligand, but they do know the N-terminus of glucagon binds deep into the <scene name='72/721535/Binding_pocket_plain/1'>binding pocket</scene>. The [https://en.wikipedia.org/wiki/Amino_acid amino acids] at the N-terminus have the ability to form [https://en.wikipedia.org/wiki/Hydrogen_bond hydrogen bonds] and [https://en.wikipedia.org/wiki/Ionic_bonding ionic interactions] involved. Here is the [https://en.wikipedia.org/wiki/Peptide_sequence amino acid sequence] of glucagon <ref name="Sequence">PMID: 11946536</ref>.
@@ Line 23: / Line 23: @@
 Many of the [https://en.wikipedia.org/wiki/Residue_(chemistry) residues] 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].
-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 <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]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> mentioned earlier that serves to hold the ECL1 and ECL2 in the proper orientation. Additionally, the salt bridges between Glu 406, Arg 173, and Arg 346, also mentioned earlier, hold the conformation together for higher affinity. Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.
+There are also many smaller residues on glucagon that support the bulky residues on the GCGR. These residues are located within the <scene name='72/721535/Binding_pocket_plain/1'>binding pocket</scene> of the 7TM <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]. This includes a [https://en.wikipedia.org/wiki/Disulfide disulfide bond] between <scene name='72/721535/Disulfide_bond_notspin/1'>Cys 294 and Cys 224</scene> 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. Finally, alpha helical structure of the stalk is imperative to the affinity and binding of the glucagon <ref name="Tips">PMID: 23863937</ref>.