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

Xudong Wang, Chris Neale, Soo-Kyung Kim, William A. Goddard and Libin Ye ()
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Xudong Wang: University of South Florida
Chris Neale: Los Alamos National Laboratory
Soo-Kyung Kim: California Institute of Technology
William A. Goddard: California Institute of Technology
Libin Ye: University of South Florida

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract 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 A2A receptor (A2AR), 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.

Date: 2023
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DOI: 10.1038/s41467-023-36971-6

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