How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?
NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC6075769?pdf=render |
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| author | Zoltan Palmai Kimberley Houenoussi Sylvia Cohen-Kaminsky Luba Tchertanov |
| author_facet | Zoltan Palmai Kimberley Houenoussi Sylvia Cohen-Kaminsky Luba Tchertanov |
| author_sort | Zoltan Palmai |
| collection | DOAJ |
| description | NMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the "going to be open state". We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target. |
| first_indexed | 2024-12-23T14:06:00Z |
| format | Article |
| id | doaj.art-c96373e004234e2bbfe43ebb7b149015 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T14:06:00Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-c96373e004234e2bbfe43ebb7b1490152022-12-21T17:44:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01138e020123410.1371/journal.pone.0201234How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors?Zoltan PalmaiKimberley HouenoussiSylvia Cohen-KaminskyLuba TchertanovNMDA-type glutamate receptors (NMDAR) are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system. NMDAR dysfunction has been found to be involved in various neurological disorders. Recent crystallographic and EM studies have shown the static structure of different states of the non-human NMDARs. Here we describe a model of a human NMDA receptor (hNMDAR) and its molecular dynamics (MD) before and after the binding of agonist ligands, glutamate and glycine. It is shown that the binding of ligands promotes a global reduction in molecular flexibility that produces a more tightly packed conformation than the unbound hNMDAR, and a higher cooperative regularity of moving. The ligand-induced synchronization of motion, identified on all structural levels of the modular hNMDA receptor is apparently a fundamental factor in channel gating. Although the time scale of the MD simulations (300 ns) was not sufficient to observe the complete gating event, the obtained data has shown the ligand-induced stabilization of hNMDAR that conforms the "going to be open state". We propose a mechanistic dynamic model of the ligand-dependent gating mechanism in the hNMDA receptor. At the binding of the ligands, the differently twisted conformations of the highly flexible receptor are stabilized in unique conformation with a linear molecular axis, which is a condition that is optimal for pore development. By searching the receptor surface, we have identified three new pockets, which are different from the pockets described in the literature as the potential and known positive allosteric modulator binding sites. A successful docking of two NMDAR modulators to their binding sites validates the model of a human NMDA receptor as a biological relevant target.http://europepmc.org/articles/PMC6075769?pdf=render |
| spellingShingle | Zoltan Palmai Kimberley Houenoussi Sylvia Cohen-Kaminsky Luba Tchertanov How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors? PLoS ONE |
| title | How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors? |
| title_full | How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors? |
| title_fullStr | How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors? |
| title_full_unstemmed | How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors? |
| title_short | How does binding of agonist ligands control intrinsic molecular dynamics in human NMDA receptors? |
| title_sort | how does binding of agonist ligands control intrinsic molecular dynamics in human nmda receptors |
| url | http://europepmc.org/articles/PMC6075769?pdf=render |
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