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  Ethanol-induced conformational fluctuations of NMDA receptors

Noori, H., Mücksch, C., & Urbassek, H. (2019). Ethanol-induced conformational fluctuations of NMDA receptors. Molecular Physics, 117(2), 200-206. doi:10.1080/00268976.2018.1504135.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-02AB-B Version Permalink: http://hdl.handle.net/21.11116/0000-0002-80A9-E
Genre: Journal Article

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Noori, HR1, 2, Author              
Mücksch, C, Author
Urbassek, HM, Author
Affiliations:
1Research Group Neuronal Convergence, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_2528694              
2Max Planck Institute for Biological Cybernetics, Max Planck Society, Spemannstrasse 38, 72076 Tübingen, DE, ou_1497794              

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 Abstract: 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.

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 Dates: 2018-072019-02
 Publication Status: Published in print
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 Identifiers: DOI: 10.1080/00268976.2018.1504135
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Title: Molecular Physics
  Other : Mol. Phys.
Source Genre: Journal
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Publ. Info: London : Taylor & Francis
Pages: - Volume / Issue: 117 (2) Sequence Number: - Start / End Page: 200 - 206 Identifier: ISSN: 0026-8976
CoNE: /journals/resource/954925264211