Meet Inspiring Speakers and Experts at our 3000+ Global Conference Series Events with over 1000+ Conferences, 1000+ Symposiums
and 1000+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business.

Explore and learn more about Conference Series : World's leading Event Organizer

Back

Stephen M. Soisson

Merck Research Laboratories, USA

Title: Structural Basis for the Cooperative Allosteric Activation of the Free Fatty Acid Receptor GPR40

Biography

Biography: Stephen M. Soisson

Abstract

Clinical 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.

References:

  1. NL Elsen, SB Patel, RE Ford, DL Hall, F Hess, H Kandula, M Kornienko et. al.  (2017) Insights into activity and inhibition from the crystal structure of human O-GlcNAcase.  Nature Chemical Biology. 13 (6):613-615.
  1. H Zhang, GW Han, A Batyuk, A Ishchenko, KL White, N Patel et. al. (2017) Structural basis for selectivity and diversity in angiotensin II receptors. Nature. 544(7650):327-332.
  1. HP Su K Rickert, C Burlein, K Narayan, M Bukhtiyarova, DM Hurzy, et. al. (2017) Structural characterization of nonactive site, TrkA-selective kinase inhibitors.    Proceedings of the National Academy of Sciences. 114(3):297-306.
  1. M Scheepstra, S Leysen, GC Van Almen, JR Miller, J Piesvaux, V Kutilek, et. al. (2015) Identification of an allosteric binding site for RORγt inhibition.  Nature communications. 6:8833.