Nanobody-Enabled Reverse Pharmacology on G-Protein-Coupled Receptors

Angewandte Chemie
Els PardonJan Steyaert

Abstract

The conformational complexity of transmembrane signaling of G-protein-coupled receptors (GPCRs) is a central hurdle for the design of screens for receptor agonists. In their basal states, GPCRs have lower affinities for agonists compared to their G-protein-bound active state conformations. Moreover, different agonists can stabilize distinct active receptor conformations and do not uniformly activate all cellular signaling pathways linked to a given receptor (agonist bias). Comparative fragment screens were performed on a β2 -adrenoreceptor-nanobody fusion locked in its active-state conformation by a G-protein-mimicking nanobody, and the same receptor in its basal-state conformation. This simple biophysical assay allowed the identification and ranking of multiple novel agonists and permitted classification of the efficacy of each hit in agonist, antagonist, or inverse agonist categories, thereby opening doors to nanobody-enabled reverse pharmacology.

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Citations

Jul 17, 2020·Chemical Communications : Chem Comm·Tiantian WuYangzhong Liu
Sep 5, 2019·Molecular Pharmacology·Vladimir BobkovMartine J Smit
Mar 4, 2020·Nature Communications·Tao CheBryan L Roth
May 23, 2019·Proceedings of the National Academy of Sciences of the United States of America·Florent ChevillardPeter Kolb
Sep 2, 2020·The Journal of Biological Chemistry·Ross W ChelohaHidde L Ploegh
Dec 21, 2020·Protein Engineering, Design & Selection : PEDS·Alexander M SevyChung-Ming Hsieh
Feb 17, 2021·Molecular Psychiatry·Ioannis MantasPer Svenningsson
Feb 10, 2020·Current Opinion in Structural Biology·Tomasz UchańskiJan Steyaert
Jul 17, 2021·Trends in Pharmacological Sciences·Ellen GulezianSunyia Hussain
Jan 9, 2020·Journal of Medicinal Chemistry·Daniel A ErlansonPaul N Mortenson

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