Ethanol-induced conformational fluctuations of NMDA receptors
| Autor: | Hamid R. Noori, Herbert M. Urbassek, Christian Mücksch |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
education.field_of_study
Ethanol 010304 chemical physics Alcohol addiction business.industry Population Biophysics Pharmacology 010402 general chemistry Condensed Matter Physics 01 natural sciences Transmembrane protein 0104 chemical sciences chemistry.chemical_compound chemistry 0103 physical sciences NMDA receptor Medicine Preventable death Physical and Theoretical Chemistry education business Molecular Biology |
| Zdroj: | Molecular Physics |
| ISSN: | 1362-3028 0026-8976 |
| Popis: | Alcohol addiction ranks among the leading global causes of preventable death and disabilities in human population. Understanding the sites of ethanol action that mediate its acute and chronic neural and behavioural effects is critical to develop appropriate treatment options for this disorder. The N-methyl-d-asparate (NMDA) receptors are ligand-gated heterotetrameric ion channels, which are known to directly interact with alcohol in a concentration-dependent manner. Yet, the exact molecular mechanisms and conformational dynamics of this interaction are not well understood. Here, we conducted a series of molecular dynamics simulations of the interaction of moderate ethanol concentrations with rat's wild-type GluN1–GluN2B NMDA Receptor under physiological conditions. The simulations suggest that glutamate or glycine alone induce an intermediate conformational state and point towards the transmembrane domain (TMD) as the site of action of ethanol molecules. Ethanol interacts by double hydrogen bonds with Trp635 and Phe638 at the transmembrane M3 helix of GluN2B. Alcohol not only reduces the pore radius of the ion channel within the TMD but also decreases accessibility of glutamate and glycine to the ligand-binding sites by altering the structure of the ligand-binding domain and significantly widening the receptor in that area. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|