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.
journal_name
Proc Natl Acad Sci U S Aauthors
Iacobucci GJ,Wen H,Helou M,Liu B,Zheng W,Popescu GKdoi
10.1073/pnas.2007511118subject
Has Abstractpub_date
2021-01-12 00:00:00issue
2eissn
0027-8424issn
1091-6490pii
2007511118journal_volume
118pub_type
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