Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation

Mitra, Argha [Mitra, Argha (Computational Che...), szerző] Biokémiai Intézet (SZBK); Sarkar, Arijit [Sarkar, Arijit (biokémia), szerző] Biokémiai Intézet (SZBK); Szabo, Marton Richard [Szabó, Márton Richárd (biokémia), szerző] Biokémiai Intézet (SZBK); Biokémiai Intézet (SZTE / SZAOK); Borics, Attila ✉ [Borics, Attila (Peptid- és fehérj...), szerző] Biokémiai Intézet (SZBK)

Angol nyelvű Szakcikk (Folyóiratcikk) Tudományos
Megjelent: BIOMOLECULES 2218-273X 2218-273X 11 (5) Paper: 670 , 16 p. 2021
  • SJR Scopus - Biochemistry: Q2
Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism, on an entirely structural basis, gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the mu opioid receptor (MOP) revealed that transmission of external stimulus to the intracellular surface of the receptor is accompanied by subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. This may entail the rearrangement of polar species and the shift of macroscopic polarization in the transmembrane domain, triggered by agonist binding. Based on our observations and numerous independent indications, we suggest amending the widely accepted theory that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface.
Hivatkozás stílusok: IEEEACMAPAChicagoHarvardCSLMásolásNyomtatás
2022-12-08 08:11