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PDBsum entry 5e94
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Membrane protein
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PDB id
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5e94
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Contents |
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214 a.a.
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224 a.a.
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110 a.a.
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100 a.a.
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References listed in PDB file
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Key reference
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Title
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Structural insight into antibody-Mediated antagonism of the glucagon-Like peptide-1 receptor.
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Authors
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S.Hennen,
J.T.Kodra,
V.Soroka,
B.O.Krogh,
X.Wu,
P.Kaastrup,
C.Ørskov,
S.G.Rønn,
G.Schluckebier,
S.Barbateskovic,
P.S.Gandhi,
S.Reedtz-Runge.
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Ref.
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Sci Rep, 2016,
6,
26236.
[DOI no: ]
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PubMed id
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Abstract
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The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G
protein-coupled receptor (GPCR) family and a well-established target for the
treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of
GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD
complex was reported previously. The first structure of a class B GPCR
transmembrane (TM) domain was solved recently, but the full length receptor
structure is still not well understood. Here we describe the molecular details
of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology
and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52)
blocked the GLP-1 binding site of the ECD directly and thereby acts as a
competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a
short peptide agonist believed to engage primarily the transmembrane and
extracellular loop region of GLP-1R, whereas functionality of an allosteric
small-molecule agonist was not inhibited. This study has implications for the
structural understanding of the GLP-1R and related class B GPCRs, which is
important for the development of new and improved therapeutics targeting these
receptors.
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