Format

Send to

Choose Destination
Nat Struct Mol Biol. 2017 Jul;24(7):570-577. doi: 10.1038/nsmb.3417. Epub 2017 Jun 5.

Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.

Author information

1
Department of Structural Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
2
Department of Screening and Protein Science, Merck Research Laboratories, West Point, Pennsylvania, USA.
3
Department of In vitro Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
4
Global Phasing Limited, Cambridge, UK.
5
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania, USA.
6
Department of Cardiometabolic Disease, Merck Research Laboratories, West Point, Pennsylvania, USA.

Abstract

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.

PMID:
28581512
DOI:
10.1038/nsmb.3417
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center