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Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating.

Title: Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating.
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Name(s): Dai, Jian, author
Zhou, Huan-Xiang, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-10-04
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: NMDA receptors are tetrameric ligand-gated ion channels. In the continuous presence of saturating agonists, NMDA receptors undergo stationary gating, in which the channel stochastically switches between an open state that permits ion conductance and a closed state that prevents permeation. The ligand-binding domains (LBDs) of the four subunits are expected to have closed clefts in the channel-open state. On the other hand, there is little knowledge about the conformational status of the LBDs in the channel-closed state during stationary gating. To probe the latter conformational status, Kussius and Popescu engineered interlobe disulfide cross-links in NMDA receptors and found that the cross-linking produced stationary gating kinetics that differed only subtly from that produced by agonist binding. These authors assumed that the cross-linking immobilized the LBDs in cleft-closed conformations, and consequently concluded that throughout stationary gating, agonist-bound LBDs also stayed predominantly in cleft-closed conformations and made only infrequent excursions to cleft-open conformations. Here, by calculating the conformational free energies of cross-linked and agonist-bound LBDs, we assess whether cross-linking actually traps the LBDs in cleft-closed conformations and delineate semiclosed conformations of agonist-bound LBDs that may potentially be thermodynamically and kinetically important during stationary gating. Our free-energy results show that the cross-linked LBDs are not locked in the fully closed form; rather, they sample semiclosed conformations almost as readily as the agonist-bound LBDs. Several lines of reasoning suggest that LBDs are semiclosed in the channel-closed state during stationary gating. Our free-energy simulations suggest possible structural details of such semiclosed LBD conformations, including intra- and intermolecular interactions that serve as alternatives to those in the cleft-closed conformations.
Identifier: FSU_pmch_27705765 (IID), 10.1016/j.bpj.2016.08.010 (DOI), PMC5052434 (PMCID), 27705765 (RID), 27705765 (EID), S0006-3495(16)30697-X (PII)
Grant Number: R01 GM058187, R35 GM118091
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052434.
Subject(s): Animals
Computer Simulation
Hydrogen Bonding
Kinetics
Models, Molecular
Protein Binding
Protein Conformation
Receptors, N-Methyl-D-Aspartate/agonists
Receptors, N-Methyl-D-Aspartate/chemistry
Receptors, N-Methyl-D-Aspartate/metabolism
Thermodynamics
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_27705765
Owner Institution: FSU
Is Part Of: Biophysical journal.
1542-0086
Issue: iss. 7, vol. 111

Choose the citation style.
Dai, J., & Zhou, H. -X. (2016). Semiclosed Conformations of the Ligand-Binding Domains of NMDA Receptors during Stationary Gating. Biophysical Journal. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_27705765