Structural basis of species-selective antagonist binding to the succinate receptor

Haffke, Matthias; Fehlmann, Dominique; Rummel, Gabriele; Boivineau, Jacques; Duckely, Myriam; Gommermann, Nina; Cotesta, Simona; Sirockin, Finton; Freuler, Felix; Littlewood‐Evans, Amanda; Kaupmann, Klemens; Jaakola, Veli-Pekka

doi:10.1038/s41586-019-1663-8

Cited by 63 publications

(68 citation statements)

References 38 publications

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“…17 Two disulfide bonds exist in the extracellular region of the receptor, with one bridge connecting TM3 with ECL2 and the other bridge connecting N terminus with TM7. 18,19 These disulfide bonds contribute to the stabilization of the receptor and formation of a ligand binding pocket with ECL2 in a close position. There are two Asn-glycosylation sites on human GPR91-Asn8 at the N terminus and Asn162 in ECL2, while on murine GPR91 only Asn4 in the N terminus is glycosylated.…”

Section: Molecular Structuresmentioning

confidence: 99%

“…25,26 Nanobody6 acts as a negative allosteric modulator, and increases the thermal stability of GPR91, which promotes the crystallization of full-length wild-type rat or humanized GPR91-Nanobody-6 complex. 18 The ECL2, specific side chains and the hydrophobic pocket are critical for ligand binding and receptor activation. The orthosteric binding pocket for endogenous succinate ligand requires that the ECL2 be in a precise position, and penetrate into to the extracellular side of helical bundle.…”

Section: The High-resolution Crystallization Of Gpr91mentioning

confidence: 99%

“…20 With the determination of humanized GPR91 crystal structure, a selective antagonist for human GPR91, NF-56-EJ40, was reported. 18 The binding site is rather clear due to the high resolution at 1.94 angstrom. The binding sites predominantly involve the acid group of the antagonist and the hydroxyl groups of Tyr83 2.64 , Tyr30 1.39 and the guanidine group in Arg281 7.39 in the TM2, TM1 and TM7 of GPR91.…”

Section: Agonists and Antagonists Of Gpr91mentioning

confidence: 99%

“…Glu18 1.27 participates in forming a hydrogen bond with the piperazine ring of NF-56-EJ40. 18 Therefore, the precise binding sites of the receptor to its natural ligand (succinate), agonists (such as cis-cyclopropane-1,2-dicarboxylic acid and cis-epoxysuccinic acid 28 ) or antagonist (NF-56-EJ40) are different although they all locate in the hydrophobic pocket.…”

Section: Agonists and Antagonists Of Gpr91mentioning

confidence: 99%

“…Relative to Glu22 1.31 and Asn274 7.32 in the human GPR91, the large side chains of Lys18 1.31 and Lys269 7.32 prevent the binding of the antagonist to rat GPR91. 18 Similarly, double mutant of Lys18 1.31 to Glu and Lys269 7.32 to Asn in rat GPR91 forms the humanized rat GPR91, which is very valuable for selective binding of antagonists against human receptor. Although antagonists may be identified and verified in this way, the actual interactions between specific antagonists and specific residues of GPR91 remain to be investigated on an individual base, 18 and probably depend on the structural conformation and active groups of individual antagonists.…”

Section: Agonists and Antagonists Of Gpr91mentioning

confidence: 99%

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GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

Xie

Zhao

et al. 2020

FASEB j.

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Succinate receptor GPR91 is one of G protein‐coupled receptors (GPCRs), and is expressed in a variety of cell types and tissues. Succinate is its natural ligand, and its activation represents that an intrinsic metabolic intermediate exerts a regulatory role on many critical life processes involving pathophysiologic mechanisms, such as innate immunity, inflammation, tissue repair, and oncogenesis. With the illustration of 3‐dimensional crystal structure of the receptor and discovery of its antagonists, it is possible to dissect the succinate‐GPR91‐G protein signaling pathways in different cell types under pathophysiological conditions. Deep understanding of the GPR91‐ligand binding mode with various agonists and antagonists would aid in elucidating the molecular basis of a spectrum of chronic illnesses, such as hypertension, diabetes, and their renal and retina complications, metabolic‐associated fatty liver diseases, such as nonalcoholic steatohepatitis and its fibrotic progression, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), age‐related macular degeneration, rheumatoid arthritis, and progressive behaviors of malignancies. With better delineation of critical regulatory role of the succinate‐GPR91 axis in these illnesses, therapeutic intervention may be developed by specifically targeting this signaling pathway with small molecular antagonists or other strategies.

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Section: Molecular Structuresmentioning

confidence: 99%

Section: The High-resolution Crystallization Of Gpr91mentioning

confidence: 99%

Section: Agonists and Antagonists Of Gpr91mentioning

confidence: 99%

Section: Agonists and Antagonists Of Gpr91mentioning

confidence: 99%

Section: Agonists and Antagonists Of Gpr91mentioning

confidence: 99%

See 3 more Smart Citations

GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

Xie

Zhao

et al. 2020

FASEB j.

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Microbiota and Metabolites as Factors Influencing Blood Pressure Regulation

Yang

Chakraborty

Mandal

et al. 2021

Comprehensive Physiology

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A Propolis‐Derived Small Molecule Tectochrysin Ameliorates Type 2 Diabetes in Mice by Activating Insulin Receptor β

Zhang,

Wu,

Shi

et al. 2023

Molecular Nutrition Food Res

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ScopePropolis has been found to decrease glucose levels and increase insulin sensitivity in type 2 diabetes. However, the active ingredient responsible for these effects and its regulating mechanism are not fully understood.Methods and resultsTo address this, molecular docking screening is used to screen the effective hypoglycemic ingredient in propolis and found that tectochrysin (TEC) has a high affinity to the insulin receptor (IR), highlighting its potential for glycemic control. In vivo tests show that TEC decreases glucose levels and enhances insulin sensitivity in db/db mice. By hyperinsulinemic euglycemic clamp test, this study further finds that TEC promotes glucose uptake in adipose tissue and skeletal muscle, as well as inhibits hepatic gluconeogenesis. Moreover, it finds that TEC promotes glucose uptake and adipocytes differentiation in 3T3‐L1 cells like insulin, suggesting that TEC exerts an insulin mimetic effect. Mechanistically, pharmacology inhibition of IRβ abolishes the effects of TEC on glucose uptake and the phosphorylation of IR. The study further demonstrates that TEC binds to and activates IRβ by targeting its E1077 and M1079.ConclusionTherefore, this study sheds light on the mechanism underlying propolis’ potential for ameliorating type 2 diabetes, offering a natural food‐derived compound as a promising therapeutic option.

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Structural basis of species-selective antagonist binding to the succinate receptor

Cited by 63 publications

References 38 publications

GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic illnesses

Microbiota and Metabolites as Factors Influencing Blood Pressure Regulation

A Propolis‐Derived Small Molecule Tectochrysin Ameliorates Type 2 Diabetes in Mice by Activating Insulin Receptor β

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