Agonist-Specific Conformations of the M-2 Muscarinic Acetylcholine Receptor Assessed by Molecular Dynamics

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F20%3A00524902" target="_blank" >RIV/67985823:_____/20:00524902 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jcim.0c00041" target="_blank" >https://doi.org/10.1021/acs.jcim.0c00041</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jcim.0c00041" target="_blank" >10.1021/acs.jcim.0c00041</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Agonist-Specific Conformations of the M-2 Muscarinic Acetylcholine Receptor Assessed by Molecular Dynamics

Popis výsledku v původním jazyce

Binding of muscarinic ligands, both antagonists and agonists, and their effects on the conformation of the M-2 acetylcholine receptor were modeled in silico and compared to experimental data. After docking of antagonists to the M2 receptor in an inactive conformation and agonists in an active conformation, conventional molecular dynamics (MD) followed accelerated MD was run. Conventional MD revealed ligand-specific interactions with the receptor. Antagonists stabilized the receptor in an inactive conformation during accelerated MD. The receptor in complex with various agonists attained different conformations specific to individual agonists. The magnitude of the TM6 movement correlated with agonist efficacy at the non-preferential G(s) pathway. The shape of the intracellular opening where the receptor interacts with a G-protein was different for the classical agonist carbachol, super-agonist iperoxo, and G(i/o)-biased partial agonists JR-6 and JR-7, being compatible with experimentally observed agonist bias at the G-protein level. Moreover, a wash-resistant binding of the unique agonist xanomeline associated with interactions with membrane lipids was formed during accelerated MD. Thus, accelerated MD is suitable for modeling of ligand-specific receptor binding and receptor conformations that is essential for the design of experiments aimed at identification of the secondary binding sites and understanding molecular mechanisms underlying receptor activation.

Název v anglickém jazyce

Agonist-Specific Conformations of the M-2 Muscarinic Acetylcholine Receptor Assessed by Molecular Dynamics

Popis výsledku anglicky

Binding of muscarinic ligands, both antagonists and agonists, and their effects on the conformation of the M-2 acetylcholine receptor were modeled in silico and compared to experimental data. After docking of antagonists to the M2 receptor in an inactive conformation and agonists in an active conformation, conventional molecular dynamics (MD) followed accelerated MD was run. Conventional MD revealed ligand-specific interactions with the receptor. Antagonists stabilized the receptor in an inactive conformation during accelerated MD. The receptor in complex with various agonists attained different conformations specific to individual agonists. The magnitude of the TM6 movement correlated with agonist efficacy at the non-preferential G(s) pathway. The shape of the intracellular opening where the receptor interacts with a G-protein was different for the classical agonist carbachol, super-agonist iperoxo, and G(i/o)-biased partial agonists JR-6 and JR-7, being compatible with experimentally observed agonist bias at the G-protein level. Moreover, a wash-resistant binding of the unique agonist xanomeline associated with interactions with membrane lipids was formed during accelerated MD. Thus, accelerated MD is suitable for modeling of ligand-specific receptor binding and receptor conformations that is essential for the design of experiments aimed at identification of the secondary binding sites and understanding molecular mechanisms underlying receptor activation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

Journal of Chemical Information and Modeling

ISSN

1549-9596

e-ISSN

—

Svazek periodika

60

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

2325-2338

Kód UT WoS článku

000529208800038

EID výsledku v databázi Scopus

2-s2.0-85084101634