Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors.
NMDA receptor
energy landscape
mutant cycle analysis
single molecule
targeted molecular dynamics
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
12 01 2021
12 01 2021
Historique:
entrez:
1
1
2021
pubmed:
2
1
2021
medline:
8
5
2021
Statut:
ppublish
Résumé
NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are currently under investigation. Very likely, the earliest steps include glutamate binding to glycine-bound receptors and subsequent constriction of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical pulling on transmembrane helices. Here, we used molecular and kinetic simulations and double-mutant cycle analyses to show that a direct chemical interaction between GluN1-I642 (on M3 helix) and GluN2A-L550 (on L1-M1 linker) stabilizes receptors after they have opened and thus represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence causes deficits in charge transfer by GluN1-I642L, a pathogenic human variant.
Identifiants
pubmed: 33384330
pii: 2007511118
doi: 10.1073/pnas.2007511118
pmc: PMC7812756
pii:
doi:
Substances chimiques
Receptors, N-Methyl-D-Aspartate
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : R01 NS052669
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097016
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS108750
Pays : United States
Informations de copyright
Copyright © 2020 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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