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

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.

• Authors: Jun Lu, Noel Byrne, John Wang, Gerard Bricogne, Frank K Brown, Harry R Chobanian, Steven L Colletti, Jerry Di Salvo, Brande Thomas-Fowlkes, Yan Guo, Dawn L Hall, Jennifer Hadix, Nicholas B Hastings, Jeffrey D Hermes, Thu Ho, Andrew D Howard, Hubert Josien, Maria Kornienko, Kevin J Lumb, Michael W Miller, Sangita B Patel, Barbara Pio, Christopher W Plummer, Bradley S Sherborne, Payal Sheth, Sarah Souza, Srivanya Tummala, Clemens Vonrhein, Maria Webb, Samantha J Allen, Jennifer M Johnston, Adam B Weinglass, Sujata Sharma, Stephen M Soisson
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 24 Issue 7 Pg. 570-577 (Jul 2017) ISSN: 1545-9985 [Electronic] United States
• PMID: 28581512 (Publication Type: Journal Article)

Chemical References

• FFAR1 protein, human
• Receptors, G-Protein-Coupled

Topics

• Allosteric Regulation
• Binding Sites
• Crystallography, X-Ray
• Humans
• Models, Molecular
• Protein Binding
• Protein Conformation
• Receptors, G-Protein-Coupled (agonists, chemistry)