Filling of a Water-free Void Explains the Allosteric Regulation of the β-adrenergic Receptor by Cholesterol

Overview

Journal Nat Chem

Specialty Chemistry

Date 2022 Aug 11

PMID 35953642

Authors

Layara Akemi Abiko

Raphael Dias Teixeira

Sylvain Engilberge

Anne Grahl

Tobias Muhlethaler

Timothy Sharpe

Stephan Grzesiek

Affiliations

Soon will be listed here.

Abstract

Recent high-pressure NMR results indicate that the preactive conformation of the β-adrenergic receptor (βAR) harbours completely empty cavities of ~100 Å volume, which disappear in the active conformation of the receptor. Here we have localized these cavities using X-ray crystallography of xenon-derivatized βAR crystals. One of the cavities is in direct contact with the cholesterol-binding pocket. Solution NMR shows that addition of the cholesterol analogue cholesteryl hemisuccinate impedes the formation of the active conformation of detergent-solubilized βAR by blocking conserved G protein-coupled receptor microswitches, concomitant with an affinity reduction of both isoprenaline and G protein-mimicking nanobody Nb80 for βAR detected by isothermal titration calorimetry. This wedge-like action explains the function of cholesterol as a negative allosteric modulator of βAR. A detailed understanding of G protein-coupled receptor regulation by cholesterol by filling of a dry void and the easy scouting for such voids by xenon may provide new routes for the development of allosteric drugs.

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