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

  • Nat Struct Mol Biol. 2017 Jul;24(7):570-577. doi: 10.1038/nsmb.3417.
Jun Lu  1 ,  Noel Byrne  2 ,  John Wang  3 ,  Gerard Bricogne  4 ,  Frank K Brown  1 ,  Harry R Chobanian  5 ,  Steven L Colletti  5 ,  Jerry Di Salvo  3 ,  Brande Thomas-Fowlkes  3 ,  Yan Guo  5 ,  Dawn L Hall  2 ,  Jennifer Hadix  2 ,  Nicholas B Hastings  3 ,  Jeffrey D Hermes  2 ,  Thu Ho  2 ,  Andrew D Howard  6 ,  Hubert Josien  5 ,  Maria Kornienko  2 ,  Kevin J Lumb  2 ,  Michael W Miller  5 ,  Sangita B Patel  1 ,  Barbara Pio  5 ,  Christopher W Plummer  5 ,  Bradley S Sherborne  1 ,  Payal Sheth  3 ,  Sarah Souza  3 ,  Srivanya Tummala  2 ,  Clemens Vonrhein  4 ,  Maria Webb  3 ,  Samantha J Allen  2 ,  Jennifer M Johnston  1 ,  Adam B Weinglass  3 ,  Sujata Sharma  2 ,  Stephen M Soisson  1
Affiliations
  • 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.
PMID: 28581512 DOI: 10.1038/nsmb.3417
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.

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