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PDBsum entry 4hj0
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Immune system
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PDB id
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4hj0
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Contents |
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92 a.a.
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206 a.a.
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210 a.a.
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PDB id:
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Immune system
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Title:
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Crystal structure of the human gipr ecd in complex with gipg013 fab at 3-a resolution
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Structure:
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Gastric inhibitory polypeptide receptor. Chain: a, b. Fragment: extra-cellular domain, unp residues 24-138. Synonym: gip-r, glucose-dependent insulinotropic polypeptide receptor. Engineered: yes. Gipg013 fab, antagonizing antibody to the gip receptor, heavy chain. Chain: p, c.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: gipr. Expressed in: escherichia coli. Expression_system_taxid: 562. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: cho.
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Resolution:
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3.00Å
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R-factor:
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0.260
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R-free:
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0.311
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Authors:
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C.Madhurantakam,P.Ravn,M.G.Gruetter,R.H.Jackson
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Key ref:
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P.Ravn
et al.
(2013).
Structural and pharmacological characterization of novel potent and selective monoclonal antibody antagonists of glucose-dependent insulinotropic polypeptide receptor.
J Biol Chem,
288,
19760-19772.
PubMed id:
DOI:
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Date:
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12-Oct-12
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Release date:
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29-May-13
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PROCHECK
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Headers
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References
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P48546
(GIPR_HUMAN) -
Gastric inhibitory polypeptide receptor from Homo sapiens
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Seq:
Struc:
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466 a.a.
92 a.a.
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DOI no:
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J Biol Chem
288:19760-19772
(2013)
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PubMed id:
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Structural and pharmacological characterization of novel potent and selective monoclonal antibody antagonists of glucose-dependent insulinotropic polypeptide receptor.
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P.Ravn,
C.Madhurantakam,
S.Kunze,
E.Matthews,
C.Priest,
S.O'Brien,
A.Collinson,
M.Papworth,
M.Fritsch-Fredin,
L.Jermutus,
L.Benthem,
M.Gruetter,
R.H.Jackson.
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ABSTRACT
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Glucose-dependent insulinotropic polypeptide (GIP) is an endogenous hormonal
factor (incretin) that, upon binding to its receptor (GIPr; a class B
G-protein-coupled receptor), stimulates insulin secretion by beta cells in the
pancreas. There has been a lack of potent inhibitors of the GIPr with prolonged
in vivo exposure to support studies on GIP biology. Here we describe the
generation of an antagonizing antibody to the GIPr, using phage and ribosome
display libraries. Gipg013 is a specific competitive antagonist with equally
high potencies to mouse, rat, dog, and human GIP receptors with a Ki of 7 nm for
the human GIPr. Gipg013 antagonizes the GIP receptor and inhibits GIP-induced
insulin secretion in vitro and in vivo. A crystal structure of Gipg013 Fab in
complex with the human GIPr extracellular domain (ECD) shows that the antibody
binds through a series of hydrogen bonds from the complementarity-determining
regions of Gipg013 Fab to the N-terminal α-helix of GIPr ECD as well as to
residues around its highly conserved glucagon receptor subfamily recognition
fold. The antibody epitope overlaps with the GIP binding site on the GIPr ECD,
ensuring competitive antagonism of the receptor. This well characterized
antagonizing antibody to the GIPr will be useful as a tool to further understand
the biological roles of GIP.
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Links
