Title:
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Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2 : Design, Synthesis, and Pharmacological Characterization
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Author:
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Doornbos, Maarten L. J.; Wang, Xuesong; Vermond, Sophie C.; Peeters, Luc; Pérez-Benito, Laura; Trabanco, Andrés A.; Lavreysen, Hilde; Cid, José María; Heitman, Laura H.; Tresadern, Gary; IJzerman, Adriaan P.
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Abstract:
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Covalent labeling of G protein-coupled receptors (GPCRs) by small molecules is a powerful approach to understand binding modes, mechanism of action, pharmacology, and even facilitate structure elucidation. We report the first covalent positive allosteric modulator (PAM) for a class C GPCR, the mGlu receptor. Three putatively covalent mGlu PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T791 7.29×30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compound in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches. |
Publication date:
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2022-10-28 |
Rights:
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open access
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https://creativecommons.org/licenses/by-nc-nd/4.0/ |
Document type:
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Article |
Published by:
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Uri:
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https://ddd.uab.cat/record/227899
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