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Limongelli_2024_Cell Press_Chem_Minute-timescale
Journal article

Minute-timescale free-energy calculations reveal a pseudo-active state in the adenosine A2A receptor activation mechanism

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  • 2024
Published in:
  • Chem. - 2024, vol. 10, no. 12
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
English 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.
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Language
  • English
Classification
Medicine
License
CC BY
Open access status
hybrid
Identifiers
Persistent URL
https://n2t.net/ark:/12658/srd1329373
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