Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics
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Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics Silvia Atanasio1 · Giuseppe Deganutti1,2 · Christopher A. Reynolds1,2 Received: 14 May 2020 / Accepted: 18 August 2020 © Springer Nature Switzerland AG 2020
Abstract The free fatty acid receptor 1 (FFAR1, formerly GPR40), is a potential G protein-coupled receptor (GPCR) target for the treatment of type 2 diabetes mellitus (T2DM), as it enhances glucose-dependent insulin secretion upon activation by endogenous long-chain free fatty acids. The presence of two allosterically communicating binding sites and the lack of the conserved GPCR structural motifs challenge the general knowledge of its activation mechanism. To date, four X-ray crystal structures are available for computer-aided drug design. In this study, we employed molecular dynamics (MD) and supervised molecular dynamics (SuMD) to deliver insights into the (un)binding mechanism of the agonist MK-8666, and the allosteric communications between the two experimentally determined FFAR1 binding sites. We found that FFAR1 extracellular loop 2 (ECL2) mediates the binding of the partial agonist MK-8666. Moreover, simulations showed that the agonists MK-8666 and AP8 are reciprocally stabilized and that AP8 influences MK-8666 unbinding from FFAR1. Keywords G protein-coupled receptors (GPCRs) · FFAR1 · GPR40 · Molecular dynamics · MD · Supervised molecular dynamics · SuMD Abbreviations FFAR1 Free fatty acid receptor 1 GPCR G protein-coupled receptor T2DM Type 2 diabetes mellitus LCFA Long-chain free fatty acids MD Molecular dynamics cMD Classic molecular dynamics SuMD Supervised molecular dynamics GLP-1 Glucagon-like peptide 1 GIP Gastric inhibitory polypeptide ICL1-3 Intracellular loop 1–3 TM1-7 Transmembrane 1–7 H8 Helix 8 TMD Transmembrane domain Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00338-6) contains supplementary material, which is available to authorized users. * Giuseppe Deganutti [email protected] 1
School of Life Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK
Present Address: Centre for Sport, Exercise and Life Sciences, Coventry University, Alison Gingell Building, Coventry CV1 5FB, UK
2
ECL1-3 Extracellular loop 1–3 POPC 1-Palmitoyl-2-oleyl-sn-glycerol-3-phosphocholine RMSD Root mean square deviations RMSF Root mean square fluctuation
Introduction The free fatty acid receptor 1 (FFAR1, formerly GPR40) is a G protein-coupled receptor (GPCR) naturally activated by saturated C12–C16 or unsaturated C18–C20 free fatty acids [1]. These long chain free fatty acids (LCFA) act as full agonists to enhance glucose-stimulated insulin secretion from pancreatic β cells [2], and secretion of the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) from intestinal enteroendocrine cells [3]. The development of drugs activating FFAR1 represent a new potential therapeutic approach against type 2 diabetes mellitus (T2DM— counti
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