Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery

Wang, Xudong; Neale, Chris; Kim, Soo-Kyung; Goddard, William A.; Ye, Libin

doi:10.1038/s41467-023-36971-6

Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery

Journal Article · Fri Mar 10 04:00:00 EST 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-36971-6· OSTI ID:2469627

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University of South Florida, Tampa, FL (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
California Institute of Technology, Pasadena, CA (United States)
University of South Florida, Tampa, FL (United States); H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL (United States)

Understanding the roles of intermediate states in signaling is pivotal to unraveling the activation processes of G protein-coupled receptors (GPCRs). However, the field is still struggling to define these conformational states with sufficient resolution to study their individual functions. Here, we demonstrate the feasibility of enriching the populations of discrete states via conformation-biased mutants. These mutants adopt distinct distributions among five states that lie along the activation pathway of adenosine A_2A receptor (A_2AR), a class A GPCR. Our study reveals a structurally conserved cation-π lock between transmembrane helix VI (TM6) and Helix8 that regulates cytoplasmic cavity opening as a “gatekeeper” for G protein penetration. A GPCR activation process based on the well-discerned conformational states is thus proposed, allosterically micro-modulated by the cation-π lock and a previously well-defined ionic interaction between TM3 and TM6. Intermediate-state-trapped mutants will also provide useful information in relation to receptor-G protein signal transduction.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; National Institutes of Health (NIH)

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 2469627

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Computational biophysics
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