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

Result code in 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>

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

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

Name of the periodical

Journal of Chemical Information and Modeling

ISSN

1549-9596

e-ISSN

—

Volume of the periodical

60

Issue of the periodical within the volume

4

Country of publishing house

US - UNITED STATES

Number of pages

14

Pages from-to

2325-2338

UT code for WoS article

000529208800038

EID of the result in the Scopus database

2-s2.0-85084101634