Cholesterol differentially modulates the activity of opioid and muscarinic receptors via a common binding site

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F25%3A00639092" target="_blank" >RIV/67985823:_____/25:00639092 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1016/j.bcp.2025.117296" target="_blank" >https://doi.org/10.1016/j.bcp.2025.117296</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bcp.2025.117296" target="_blank" >10.1016/j.bcp.2025.117296</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Cholesterol differentially modulates the activity of opioid and muscarinic receptors via a common binding site

Popis výsledku v původním jazyce

G protein-coupled receptors (GPCRs) are membrane proteins that represent the largest and most therapeutically targeted receptor class, accounting for 30% of currently marketed drugs. Two binding motifs for membrane cholesterol, the cholesterol recognition amino acid consensus (CRAC) domain and the cholesterol consensus motif (CCM), have been postulated. Using a simulation of the molecular dynamics of cholesterol association with the receptor, we predicted the binding of membrane cholesterol to non-canonical sites, distinct from CRAC and CCM, at muscarinic and opioid receptors. We identified a binding site common to muscarinic and opioid receptors at TM6, with arginine 6.35 as the major residue. Membrane cholesterol depletion mimics the effects of R6.35 mutations, confirming its role in receptor modulation. Targeting cholesterol-binding sites offers novel pharmacotherapeutic strategies, including tissue-specific sterol-based modulation.

Název v anglickém jazyce

Cholesterol differentially modulates the activity of opioid and muscarinic receptors via a common binding site

Popis výsledku anglicky

G protein-coupled receptors (GPCRs) are membrane proteins that represent the largest and most therapeutically targeted receptor class, accounting for 30% of currently marketed drugs. Two binding motifs for membrane cholesterol, the cholesterol recognition amino acid consensus (CRAC) domain and the cholesterol consensus motif (CCM), have been postulated. Using a simulation of the molecular dynamics of cholesterol association with the receptor, we predicted the binding of membrane cholesterol to non-canonical sites, distinct from CRAC and CCM, at muscarinic and opioid receptors. We identified a binding site common to muscarinic and opioid receptors at TM6, with arginine 6.35 as the major residue. Membrane cholesterol depletion mimics the effects of R6.35 mutations, confirming its role in receptor modulation. Targeting cholesterol-binding sites offers novel pharmacotherapeutic strategies, including tissue-specific sterol-based modulation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/LX22NPO5107" target="_blank" >LX22NPO5107: Národní ústav pro neurologický výzkum</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochemical Pharmacology

ISSN

0006-2952

e-ISSN

1873-2968

Svazek periodika

242

Číslo periodika v rámci svazku

Pt1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

16

Strana od-do

117296

Kód UT WoS článku

001565629700002

EID výsledku v databázi Scopus

2-s2.0-105014757680