Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors.
Proc Natl Acad Sci U S A
; 118(2)2021 01 12.
Article
em En
| MEDLINE
| ID: mdl-33384330
ABSTRACT
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Receptores de N-Metil-D-Aspartato
/
Simulação de Dinâmica Molecular
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article