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PDBsum entry 6vcb
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Signaling protein/membrane protein
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PDB id
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6vcb
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Contents |
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378 a.a.
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31 a.a.
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223 a.a.
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339 a.a.
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59 a.a.
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128 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 insights into probe-Dependent positive allosterism of the glp-1 receptor.
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Authors
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A.B.Bueno,
B.Sun,
F.S.Willard,
D.Feng,
J.D.Ho,
D.B.Wainscott,
A.D.Showalter,
M.Vieth,
Q.Chen,
C.Stutsman,
B.Chau,
J.Ficorilli,
F.J.Agejas,
G.R.Cumming,
A.Jiménez,
I.Rojo,
T.S.Kobilka,
B.K.Kobilka,
K.W.Sloop.
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Ref.
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Nat Chem Biol, 2020,
16,
1105-1110.
[DOI no: ]
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PubMed id
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Abstract
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Drugs that promote the association of protein complexes are an emerging
therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR)
ligand that stabilizes an active state conformation by cooperatively binding
both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'.
LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to
increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of
GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and
GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of
the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric
Gs. The modulator binds high in the helical bundle at an interface
between TM1 and TM2, allowing access to the peptide ligand. Pharmacological
characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36)
versus oxyntomodulin that is driven by a single residue. Our findings expand
protein-protein modulation drug discovery to uncompetitive, active state
stabilizers for peptide hormone receptors.
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