Abstract
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 µs 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.
Highlights
Pharmacological experiments have suggested the existence of several distinct excitatory amino acid receptors that may be distinguished by the use of selective agonists and antagonists withN-methyl-d-aspartic acid (NMDA) being a specific agonist for one type of receptor [1]
Using an aggregate of nearly 1 μs of unbiased all-atom molecular dynamics (MD) simulations in an implicit membrane and solvent, we investigated the molecular mechanisms of the receptor transition from the state with the transmembrane domain and the ion channel in the open configuration to the relaxed unliganded state with the channel closed
The native NMDA receptors (NMDARs) is highly glycosylated and it was shown by experimental as well as theoretical studies that the glycans are essential for correct trafficking of the mature receptor to the cell membrane [58] and modulation of the affinity and kinetics of interactions between ligand binding domain (LBD) and their ligands [42]
Summary
N-methyl-d-aspartic acid (NMDA) being a specific agonist for one type of receptor [1] Later, these results were confirmed by molecular cloning and it was shown that NMDA receptors (NMDARs) are hetero-tetramers, composed of four subunits—two GluN1 and two GluN2A-D and/or GluN3A-B subunits [2,3,4,5,6]. Glutamate and glycine binding to the respective ligand-binding domains at the GluN2 and GluN1 subunit promote conformational changes leading to the opening of the channel pore that is permeable to sodium and calcium [14]. Kinetic analysis of macroscopic responses induced by glutamate in the presence of a saturating concentration of glycine reveal a minimum of five states that describe receptor agonist activation, desensitization, and channel opening [15,16]. Single-channel analysis shows additional states for agonist-bound receptors, which includes a minimum of five closed states and at least two open states [21,22,23,24,25,26]
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