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Visualizing agonist-induced M2 receptor activation regulated by aromatic ring dynamics.

Zhou Gong1, Xu Zhang1, Maili Liu1

  • 1State Key Laboratory of Magnetic Resonance Spectroscopy and Imaging, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China.

Proceedings of the National Academy of Sciences of the United States of America
|March 7, 2025
PubMed
Summary
This summary is machine-generated.

Molecular dynamics simulations reveal the M2 muscarinic acetylcholine receptor (M2R) activation pathway. Ligand binding induces sequential structural changes, detailing how receptor activation and agonist efficacy are encoded.

Keywords:
G protein-coupled receptoractivationdynamicsligand efficacy

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Pharmacology

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets, but their activation mechanisms remain incompletely understood.
  • Resolving GPCR structures provides static snapshots, yet the dynamic transition from inactive to active states requires further investigation.

Purpose of the Study:

  • To elucidate the dynamic conformational changes of the M2 muscarinic acetylcholine receptor (M2R) during agonist-induced activation.
  • To explore how ligand binding modulates M2R conformational dynamics at an atomic level.

Main Methods:

  • Comprehensive molecular dynamics simulations were employed to study M2R.
  • Analysis focused on structural changes, intermediate conformations, and key residue dynamics.

Main Results:

  • A sequential activation pathway for M2R was observed, involving orthosteric binding site contraction and TM6 opening.
  • Two distinct activation intermediates were identified, differing from apo-GPCR structures.
  • Specific residue dynamics (W400, F396) and side-chain rotamers (Y206) correlate with activation and agonist efficacy.

Conclusions:

  • The study provides atomic-level insights into the M2R activation pathway triggered by agonists.
  • A mechanism is proposed where ligand efficacy is encoded in aromatic ring dynamics, influencing receptor activation.