Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor

Donthamsetti, Prashant; Konrad, David B.; Hetzler, Belinda; Fu, Zhu; Trauner, Dirk; Isacoff, Ehud Y.

doi:10.1021/jacs.1c02586

Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor

Journal Article · Fri Jun 11 00:00:00 EDT 2021 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.1c02586· OSTI ID:1816033

Donthamsetti, Prashant ^[1]; ^[2]; Hetzler, Belinda ^[3]; Fu, Zhu ^[4]; ^[3]; ^[5]

Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; OSTI
Ludwig-Maximilians-Universität München (Germany). Dept. of Pharmacy
New York Univ. (NYU), NY (United States). Dept. of Chemistry
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Univ. of California, Berkeley, CA (United States).Helen Wills Neuroscience Inst.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics & Integrated Bioimaging Division

G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G_i/o-coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.

View Accepted Manuscript (DOE)

Sponsoring Organization:: European Research Council (ERC); Friedrich-Ebert-Foundation; National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; Weill Neurohub

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1816033

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 24 Vol. 143; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor

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