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Volume 10, Issue 8 (Suppl)

J Proteomics Bioinform, an open access journal

ISSN: 0974-276X

Structural Biology 2017

September 18-20, 2017

International Conference on

Structural Biology

September 18-20, 2017 Zurich, Switzerland

Stephen M Soisson, J Proteomics Bioinform 2017, 10:8(Suppl)

DOI: 10.4172/0974-276X-C1-0100

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

Stephen M Soisson

Merck Research Laboratories, USA

linical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor GPR40 enhance glucose-

dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Recently

identified, full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional

efficacy. Our recent studies have led to a 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the

partial agonist MK-8666 and an AgoPAM. Surprisingly, the structure reveals 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). These structural rearrangements, along with AgoPAM

binding, appear to trigger the transition of 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.

Biography

Stephen M Soisson, PhD is a Director of Biochemical Engineering and Structure at Merck Research Laboratories in West Point, Pennsylvania (USA). With 25+

years of structural biology experience, he has focused research on elucidating the structural aspects of biological regulatory mechanisms, and applying these

insights in the area of structure-based drug design. He has served on the scientific advisory boards of the Structural Genomics Consortium, and the GPCR

Consortium.

stephen_soisson@merck.com

Figure1:

Structural basis for the cooperative

allosteric activation of the free fatty acid receptor

GPR40