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PDBsum entry 5vex
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Signaling protein
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PDB id
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5vex
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References listed in PDB file
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Key reference
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Title
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Human glp-1 receptor transmembrane domain structure in complex with allosteric modulators.
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Authors
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G.Song,
D.Yang,
Y.Wang,
C.De graaf,
Q.Zhou,
S.Jiang,
K.Liu,
X.Cai,
A.Dai,
G.Lin,
D.Liu,
F.Wu,
Y.Wu,
S.Zhao,
L.Ye,
G.W.Han,
J.Lau,
B.Wu,
M.A.Hanson,
Z.J.Liu,
M.W.Wang,
R.C.Stevens.
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Ref.
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Nature, 2017,
546,
312-315.
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PubMed id
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Abstract
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The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR)
are members of the secretin-like class B family of G-protein-coupled receptors
(GPCRs) and have opposing physiological roles in insulin release and glucose
homeostasis. The treatment of type 2 diabetes requires positive modulation of
GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a
glucose-dependent manner. Here we report crystal structures of the human GLP-1R
transmembrane domain in complex with two different negative allosteric
modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution,
respectively. The structures reveal a common binding pocket for negative
allosteric modulators, present in both GLP-1R and GCGR and located outside
helices V-VII near the intracellular half of the receptor. The receptor is in an
inactive conformation with compounds that restrict movement of the intracellular
tip of helix VI, a movement that is generally associated with activation
mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies
indicate that agonist positive allosteric modulators target the same general
region, but in a distinct sub-pocket at the interface between helices V and VI,
which may facilitate the formation of an intracellular binding site that
enhances G-protein coupling.
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