NMDA Receptor Opening and Closing-Transitions of a Molecular Machine Revealed by Molecular Dynamics

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F19%3A00517459" target="_blank" >RIV/67985823:_____/19:00517459 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/86652036:_____/19:00517484 RIV/00216224:14310/19:00113388 RIV/00159816:_____/19:00072499

Výsledek na webu

<a href="https://doi.org/10.3390/biom9100546" target="_blank" >https://doi.org/10.3390/biom9100546</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/biom9100546" target="_blank" >10.3390/biom9100546</a>

Jazyk výsledku

angličtina

Název v původním jazyce

NMDA Receptor Opening and Closing-Transitions of a Molecular Machine Revealed by Molecular Dynamics

Popis výsledku v původním jazyce

We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-D-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 mu s of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the “clamshell” motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD-TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine.

Název v anglickém jazyce

NMDA Receptor Opening and Closing-Transitions of a Molecular Machine Revealed by Molecular Dynamics

Popis výsledku anglicky

We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-D-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 mu s of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the “clamshell” motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD-TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

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

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

Biomolecules

ISSN

2218-273X

e-ISSN

—

Svazek periodika

9

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

17

Strana od-do

546

Kód UT WoS článku

000497726800038

EID výsledku v databázi Scopus

2-s2.0-85072781240