Free fatty acid receptors: structural models and elucidation of ligand binding interactions

BMC Structural Biology
Irina G Tikhonova, Elena Poerio

Abstract

The free fatty acid receptors (FFAs), including FFA1 (orphan name: GPR40), FFA2 (GPR43) and FFA3 (GPR41) are G protein-coupled receptors (GPCRs) involved in energy and metabolic homeostasis. Understanding the structural basis of ligand binding at FFAs is an essential step toward designing potent and selective small molecule modulators. We analyse earlier homology models of FFAs in light of the newly published FFA1 crystal structure co-crystallized with TAK-875, an ago-allosteric ligand, focusing on the architecture of the extracellular binding cavity and agonist-receptor interactions. The previous low-resolution homology models of FFAs were helpful in highlighting the location of the ligand binding site and the key residues for ligand anchoring. However, homology models were not accurate in establishing the nature of all ligand-receptor contacts and the precise ligand-binding mode. From analysis of structural models and mutagenesis, it appears that the position of helices 3, 4 and 5 is crucial in ligand docking. The FFA1-based homology models of FFA2 and FFA3 were constructed and used to compare the FFA subtypes. From docking studies we propose an alternative binding mode for orthosteric agonists at FFA1 and FFA2, involving the...Continue Reading

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Citations

Jun 15, 2016·Chemical Reviews·Graeme MilliganBrian D Hudson
Feb 17, 2017·Future Medicinal Chemistry·Pawin PongkorpsakolChatchai Muanprasat
Jan 25, 2017·Basic Research in Cardiology·Nikolina JovancevicH Hatt
Jun 2, 2017·Journal of Medicinal Chemistry·Anders Højgaard HansenTrond Ulven
Oct 25, 2017·Future Medicinal Chemistry·Mariateresa BadolatoFrancesca Aiello
Jun 29, 2017·Pharmacological Reviews·Anna CooperAndrea J Vernall
Nov 15, 2019·CNS & Neurological Disorders Drug Targets·Neha M ChitreKevin S Murnane
Aug 28, 2020·Journal of Computer-aided Molecular Design·Silvia AtanasioChristopher A Reynolds
Jun 6, 2017·Nature Structural & Molecular Biology·Jun LuStephen M Soisson

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Software Mentioned

Prime
SiteMap
Glide
Maestro
HHpred
MacroModel
CLUSTALW
InducedFit
VMD
Chimera

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