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

Lu, Jun; Byrne, Noel; Wang, John; Bricogne, G.; Brown, Frank K.; Chobanian, Harry R.; Colletti, Steven L.; Salvo, Jerry Di; Thomas-Fowlkes, Brande; Guo, Yan; Hall, Dawn L.; Hadix, Jennifer; Hastings, Nicholas B.; Hermes, Jeffrey D.; Ho, Thu; Howard, Andrew D.; Josien, Hubert; Kornienko, Maria; Lumb, Kevin J.; Miller, Mark W.; Patel, Sangita; Pio, Barbara; Plummer, Christopher W.; Sherborne, Bradley S.; Sheth, Payal R.; Souza, Sarah; Tummala, Srivanya; Vonrhein, Clemens; Webb, Maria L.; Allen, Samantha J.; Johnston, Jennifer M.; Weinglass, Adam B.; Sharma, Sujata; Soisson, S.M.

doi:10.1038/nsmb.3417

Cited by 161 publications

(178 citation statements)

References 42 publications

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“…The presence of energetically stable meta‐binding sites, alternative to the canonical orthosteric one, could open the scenario in which a ligand can simultaneously recognize the same receptor with a stoichiometry other than 1 : 1. In recent crystallographic structures, class A GPCRs contemporary bound orthosteric and allosteric ligands . Moreover, the development of dualsteric agents corroborates this intriguing scenario.…”

Section: Introductionmentioning

confidence: 84%

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Deganutti

Salmaso

Moro

2018

Molecular Informatics

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One of the most largely accepted concepts in the G protein-coupled receptors (GPCRs) field is that the ligand, either agonist or antagonist, recognizes its receptor with a stoichiometry of 1 : 1. Recent experimental evidence, reporting ternary complexes formed by GPCR:orthosteric: allosteric ligands, has complicated the ligand-receptor 1 : 1 binding scenario. Molecular modeling simulations have been used to retrieve insights on the whole ligand-receptor recognition process, beyond information on the final bound state provided by experimental techniques. The simulation of adenosine binding pathways towards the A adenosine receptor highlighted the presence of alternative binding sites (meta-binding sites) beside the canonical orthosteric one, mainly in proximity to the extracellular vestibule. In light of all these considerations, we investigated the possibility that a second molecule of adenosine engages its receptor when this is already in the holo form, generating a ternary complex with a stoichiometry of 2 : 1. Unexpectedly, supervised molecular dynamics (SuMD) simulations showed that the A adenosine receptor could bind the second molecule of adenosine in one of the possible meta-binding sites as well as into its orthosteric site. The formation of this ternary complex, which favored the formation of the intracellular "ionic lock" between R102 (3.50) and E228 (6.30), could putatively be framed in the context of a negative allosteric regulation.

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Section: Introductionmentioning

confidence: 84%

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Deganutti

Salmaso

Moro

2018

Molecular Informatics

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“…3). A spectacular result of recent crystallography, and one case of a large DNA-encoded library screening 30 , is that two other allosteric sites on GPCRs are targetable by small molecules: the intracellular region where G protein binds 31,32 and an intramembrane region on the outer surface of the helical bundle 33,34 . These sites appear conserved among family A GPCRs, suggesting that they may be broadly targeted.…”

Section: Allostery and Biasmentioning

confidence: 99%

Discovery of new GPCR ligands to illuminate new biology

2017

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Although a plurality of drugs target G-protein-coupled receptors (GPCRs), most have emerged from classical medicinal chemistry and pharmacology programs and resemble one another structurally and functionally. Though effective, these drugs are often promiscuous. With the realization that GPCRs signal via multiple pathways, and with the emergence of crystal structures for this family of proteins, there is an opportunity to target GPCRs with new chemotypes and confer new signaling modalities. We consider structure-based and physical screening methods that have led to the discovery of new reagents, focusing particularly on the former. We illustrate their use against previously untargeted or orphan GPCRs, against allosteric sites, and against classical orthosteric sites that selectively activate one downstream pathway over others. The ligands that emerge are often chemically novel, which can lead to new biological effects.

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“…Molecular Modeling. Molecular modeling and docking have been performed using the recent co-crystal structure of hGPR40 in complex with MK-8666 and AgoPAM AP8 (PDB code 5TZY) (Lu et al, 2017). Molecular Operating Environment 2015.1001 (Chemical Computing Group Inc., Montreal, QC, Canada) was used for loop modeling, energy minimization (AMBER10:EHT forcefield and Born solvation model), and rescoring of the docking poses.…”

Section: Methodsmentioning

confidence: 99%

“…Since then, numerous full agonists with superior efficacy both in vitro and in vivo compared with fasiglifam have been reported (Defossa and Wagner, 2014;Li et al, 2016). Interestingly, these full agonists bind to a recently identified binding site, distinct from previously predicted pockets, and different from that of endogenous fatty acids and fasiglifam or other partial agonists (Lin et al, 2012;Defossa and Wagner, 2014;Hauge et al, 2014;Srivastava et al, 2014;Lu et al, 2017). The presence of multiple binding sites suggests conformational plasticity, highlighting a potential for biased agonism (Kenakin et al, 2012;Kenakin and Christopoulos, 2013;Costa-Neto et al, 2016;Rankovic et al, 2016).…”

Section: Introductionmentioning

confidence: 96%

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

et al. 2018

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GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gq and Gi2 pathways, and in contrast to fasiglifam Compound A also induced G12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The G/G-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that G12/G13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.

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

Cited by 161 publications

References 42 publications

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Could Adenosine Recognize its Receptors with a Stoichiometry Other than 1 : 1?

Discovery of new GPCR ligands to illuminate new biology

GPR40-Mediated Gα12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets

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