Structural basis for GPR40 allosteric agonism and incretin stimulation

Abstract

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.

Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations

“…The A occl2 and A open models (expected to be inactive and active toward Gq, respectively) primarily differ in the position of TM5 and the large inward movement of the ICL2 label in A occl2 , though there may be additional distinguishing features that our current spin label pairs are not positioned to detect. Interestingly, recent structural data and MD simulations have highlighted the role of ICLs in transducers' binding mechanisms (Ho et al, 2018;Latorraca et al, 2018).…”

MultiBac: Baculovirus-Mediated Multigene DNA Cargo Delivery in Insect and Mammalian Cells

“…Insect cells appear to be well suited for producing heterologous G-protein coupled receptors, consequently, many GPCRs are being produced by BICS. The MultiBac system we have developed is contributing to this trend, and a selection of recent high-impact ligand-bound GPCR structures, enabled by MultiBac [69,70,71], is depicted below (Figure 4b–d). As hetero-oligomeric GPCRs and GPCRs complexed with accessory proteins come increasingly in focus, we expect the impact of MultiBac to significantly increase in this vibrant research field [72,73].…”

Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1

“…Recent data are still highly polarized, with some authors supporting ( 255 ), and others disproving this ( 256 ), or even indicating that GPR40 protects β-cells from lipotoxicity ( 257 ) rendering difficult to draw any conclusive mechanistic involvement in healthy and diabetic individuals. Nonetheless, the activation of this receptor with FFAs has demonstrated to induce the secretion of incretins ( 79 , 258 ) glucagon ( 78 , 250 ) and partially glucose-stimulated insulin ( 259 , 260 ) reducing food intake, and lowering body weight in animals models ( 261 ). Mice without a functional GPR40 display an impaired CCK and GLP-1 secretion after an oil gavage, while surprisingly animals deficient for GPR120 display a normal corn oil-induced GLP-1 secretion ( 80 , 262 ).…”

“…GPR40 is coupled to both Gq and Gs proteins and in vivo studies suggest how signaling through both these cascades elicits the most powerful GLP-1 secretion ( 258 ). Ligands that bind GPR40 and activate predominantly only the Gq pathway are not good GLP-1 secretagogues.…”