Minute-timescale free-energy calculations reveal a pseudo-active state in the adenosine A2A receptor activation mechanism
Additional information
Authors
D’Amore V. M.,
Conflitti P.,
Marinelli L.,
Limongelli V.
Type
Journal Article
Year
2024
Language
English
Abstract
G protein-coupled receptors (GPCRs) are membrane proteins targeted by over one-third of marketed drugs. Understanding their activation mechanism is essential for precise regulation of drug pharmacological response. In this work, we elucidate the conformational landscape of the adenosine A2A receptor (A2AR) activation mechanism in its basal apo form and under different ligand-bound conditions through minute-timescale free-energy calculations. We identified a pseudo-active state (pAs) of the A2AR apo form, stabilized by specific "microswitch" residues, including a salt bridge established between the conserved residues R5.66 and E6.30. The pAs enables A2AR to couple with Gs protein upon rearrangement of the intracellular end of transmembrane helix 6, providing unprecedented structural insights into receptor function and signaling dynamics. Our simulation protocol is versatile and can be adapted to study the activation of any GPCRs, potentially making it a valuable tool for drug design and "biased signaling" studies.
Keywords
Molecular dynamics, Metadynamics, Free-energy calculations, Path collective variables, G protein-coupled receptors, Adenosine A2A receptor, GPCRs activation mechanism, GPCRs functional dynamics, GPCRs microswitches, G protein coupling
Journal
Chem
Volume
10
Number ( Month )
12
Diffusion
License
CC BY
Visibility
Public
Status open access
Hybrid
