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

5 years ago

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

Yan Guo, Brande Thomas-Fowlkes, Srivanya Tummala, Nicholas B Hastings, Gerard Bricogne, Maria Webb, Kevin J Lumb, Steven L Colletti, Andrew D Howard, Sujata Sharma, Hubert Josien, Harry R Chobanian, Samantha J Allen, Payal Sheth, Jeffrey D Hermes, Frank K Brown, Sangita B Patel, Dawn L Hall, Stephen M Soisson, Noel Byrne, Clemens Vonrhein, Maria Kornienko, Barbara Pio, Thu Ho, John Wang, Christopher W Plummer, Jennifer Hadix, Jerry Di Salvo, Jun Lu, Jennifer M Johnston, Sarah Souza, Michael W Miller, Adam B Weinglass, Bradley S Sherborne

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.

Publisher URL: http://dx.doi.org/10.1038/nsmb.3417

DOI: 10.1038/nsmb.3417