Sandbox Reserved 1180

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===Glucagon Binding===
===Glucagon Binding===
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[[Image:Protter GLR HUMAN.png |300 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"/>]]
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[[Image:Movie Frame 6.png |200 px|right|thumb|Fig. 2: <scene name='72/721552/Glucagon_binding/3'>Deep, central cavity</scene> functioning as anchoring site for glucagon's n-terminal residues.]][[Image:Glucagon with Q3 and N-terminus.png |200 px|right|thumb|Fig. 3: Surface visualization of glucagon visualizing the three dimensional shape of the N-terminal tail that interacts with the binding site of GCGR central cavity.]] The large, soluble N-terminal extracellular domains (ECD) of GCGR provide initial ligand selectivity with the deep, ligand pocket (Fig. 2) of the TMD providing secondary recognition.<ref name= "Yang 2015"/> In a comprehensive mutagenesis and glucagon-binding study, a total of 129 mutations of GCGR were tested. 41 of these covering 28 different locations in the GCGR TMD 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 (Tyr 138) to deep within the 7TM core (Glu 362), encompassing positions along ECL1, ECL2 and ECL3 and helices I, II, III, V, VI and VII.
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The large, soluble N-terminal extracellular domains (ECD) of GCGR provide initial ligand selectivity with the deep, ligand pocket (Fig. 2) of the TMD providing secondary recognition.<ref name= "Yang 2015"/>
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Mutagenesis and photo cross-linking studies determined essential, conserved residues in glucagon and have been <scene name='72/727091/Glucagon_important_residues/2'>labeled and colored</scene> in red.<ref name= "Siu 2013"/> Glucagon residues His 1, Gln 3, Phe 6, and Tyr 10 are critical to successful binding interaction with the GCGR while others are important for structural rigidity. The n-terminus of glucagon (Fig. 3) leads to a protuberance that fits into the deep, interior cavity of the GCGR 7TMD (Fig. 2) where four residues reside that play strong roles in ligand binding affinity. There is a <scene name='72/721552/Glucagon_binding_zoomed_in/1'>narrow neck</scene> to the entrance of the cavity, providing a firm anchor during peptide docking.
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[[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"/>]]
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In a comprehensive mutagenesis and glucagon-binding study, a total of 129 mutations of GCGR were tested. 41 of these covering 28 different locations in the GCGR TMD 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 (Tyr 138) to deep within the 7TM core (Glu 362), encompassing positions along ECL1, ECL2 and ECL3 and helices I, II, III, V, VI and VII.[[Image:Movie Frame 6.png |200 px|center|thumb|Fig. 2: <scene name='72/721552/Glucagon_binding/3'>Deep, central cavity</scene> functioning as anchoring site for glucagon's n-terminal residues.]][[Image:Glucagon with Q3 and N-terminus.png |200 px|right|thumb|Fig. 3: Surface visualization of glucagon visualizing the three dimensional shape of the N-terminal tail that interacts with the binding site of GCGR central cavity.]]
 
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Mutagenesis and photo cross-linking studies determined essential, conserved residues in glucagon and have been <scene name='72/727091/Glucagon_important_residues/2'>labeled and colored</scene> in red.<ref name= "Siu 2013"/> Glucagon residues His 1, Gln 3, Phe 6, and Tyr 10 are critical to successful binding interaction with the GCGR while others are important for structural rigidity. The n-terminus of glucagon (Fig. 3) leads to a protuberance that fits into the deep, interior cavity of the GCGR 7TMD (Fig. 2) where four residues reside that play strong roles in ligand binding affinity. There is a <scene name='72/721552/Glucagon_binding_zoomed_in/1'>narrow neck</scene> to the entrance of the cavity, providing a firm anchor during peptide docking.
 

Revision as of 04:34, 22 April 2016

Glucagon G protein-coupled receptor

PDB ID 4L6R

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