Sandbox Reserved 1180: Difference between revisions

From Proteopedia
Jump to navigationJump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 28: Line 28:
Most notably, class B GPCRs contain a <scene name='72/727091/Corticotropin_glucagon_aligned/1'>prominent central splay</scene> which is solvent filled and accessible from the extracellular side.  This central splay is notably absent <scene name='72/727091/B2-adrenergic_glucagon_aligned/9'>from other GPCRs</scene>, and represents a tantalizing target for agonists/antagonists.<ref name= "Hollenstein 2014"/>
Most notably, class B GPCRs contain a <scene name='72/727091/Corticotropin_glucagon_aligned/1'>prominent central splay</scene> which is solvent filled and accessible from the extracellular side.  This central splay is notably absent <scene name='72/727091/B2-adrenergic_glucagon_aligned/9'>from other GPCRs</scene>, and represents a tantalizing target for agonists/antagonists.<ref name= "Hollenstein 2014"/>


[[Image:Protter GLR HUMAN.png |400 px|left|thumb|Fig. 1: Snake Plot of GCGR TMD. Residues of particular importance in glucagon binding affinity are found in green, yellow, and black. Residues in red are the location of critical disulfide bonds, while blue residues were found to be highly conserved across all class B GPCRs.<ref name= "Siu 2013"/>]]
Because of the difficulty in stabilizing and crystallizing Class B TMDs, very little is known about the conformational changes that transduce cell signals endogenously. GCGR is known to regulate additional signal pathways through the adoption of differing receptor conformations and to interact with receptor activity-modifying proteins (RAMPs) altering the signaling bias of the receptor.<ref name= "Xu 2009"/>


In a comprehensive mutagenesis and glucagon-binding study, a total of 129 mutations were tested.  41 of these covering 28 different locations in the GCGR were found to have at least a fourfold decrease in glucagon binding affinity<ref name= "Siu 2013"/>. (see Fig. 1)  It is the face of the central cavity that harbors the majority of the residues which play an important role in glucagon binding.<ref name= "Siu 2013"/>  The binding site was shown to be a dynamic area traveling from the middle of the stalk region to deep within the 7TM core. (See Fig. 2)  [[Image:Movie Frame 8.png |275 px|right|thumb|Fig. 2: Relationship between Tyr138 and Glu362 - residues spanning the height of the glucagon binding pocket in GCGR.]]  The binding site encompasses positions along ECL1, ECL2 and ECL3 and helices I, II, III, V, VI and VII, while extending deep in the 7TM cavity.


Glucagon itself carries <scene name='72/727091/Glucagon_important_residues/2'>several residues</scene> essential to the proper binding of glucagon to the GCGR. 
===Glucagon Binding===


[[Image:Protter GLR HUMAN.png |400 px|left|thumb|Fig. 1: Snake Plot of GCGR TMD. Residues of particular importance in glucagon binding affinity are found in green, yellow, and black.  Residues in red are the location of critical disulfide bonds, while blue residues were found to be highly conserved across all class B GPCRs.<ref name= "Siu 2013"/>]]


Because of the difficulty in stabilizing and crystallizing Class B TMDs, very little is known about the conformational changes that transduce cell signals endogenously. GCGR is known to regulate additional signal pathways through the adoption of differing receptor conformations and to interact with receptor activity-modifying proteins (RAMPs) altering the signaling bias of the receptor.<ref name= "Xu 2009"/>
In a comprehensive mutagenesis and glucagon-binding study, a total of 129 mutations were tested.  41 of these covering 28 different locations in the GCGR were found to have at least a fourfold decrease in glucagon binding affinity<ref name= "Siu 2013"/>. (see Fig. 1)  It is the face of the central cavity that harbors the majority of the residues which play an important role in glucagon binding.<ref name= "Siu 2013"/> The binding site was shown to be a dynamic area traveling from the middle of the stalk region to deep within the 7TM core. (See Fig. 2)  [[Image:Movie Frame 8.png |275 px|right|thumb|Fig. 2: Relationship between Tyr138 and Glu362 - residues spanning the height of the glucagon binding pocket in GCGR.]]  The binding site encompasses positions along ECL1, ECL2 and ECL3 and helices I, II, III, V, VI and VII, while extending deep in the 7TM cavity.
 


===Glucagon Binding===
Glucagon itself carries <scene name='72/727091/Glucagon_important_residues/2'>several residues</scene> essential to the proper binding of glucagon to the GCGR.  Residues His 1, Gln 3, Phe 6, and Tyr 10 are critical to successful ligand




Retrieved from "https://proteopedia.org/Sandbox_Reserved_1180"