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Modeling anesthetic binding sites within the glycine alpha one receptor based on prokaryotic ion channel templates: the problem with TM4
Stanford University.
Stockholm University.
Stanford University.
Stockholm University.ORCID iD: 0000-0002-2734-2794
2010 (English)In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 50, no 12, 2248-2255 p.Article in journal (Refereed) Published
Abstract [en]

Ligand-gated ion channels (LGICs) significantly modulate anesthetic effects. Their exact molecular structure remains unknown. This has led to ambiguity regarding the proper amino acid alignment within their 3D structure and, in turn, the location of any anesthetic binding sites. Current controversies suggest that such a site could be located in either an intra- or intersubunit locale within the transmembrane domain of the protein. Here, we built a model of the glycine alpha one receptor (GlyRa1) based on the open-state structures of two new high-resolution ion channel templates from the prokaryote, Gloebacter violaceus (GLIC). Sequence scoring suggests reasonable homology between GlyRa1 and GLIC. Three of the residues notable for modulating anesthetic action are on transmembrane segments 1-3 (TM1-3): (ILE229, SER 267, and ALA 288). They line an intersubunit interface, in contrast to previous models. However, residues from the fourth transmembrane domain (TM4) that are known to modulate a variety of anesthetic effects are quite distant from this putative anesthetic binding site. While this model can account for a large proportion of the physicochemical data regarding such proteins, it cannot readily account for the alterations on anesthetic effects that are due to mutations within TM4.

Place, publisher, year, edition, pages
2010. Vol. 50, no 12, 2248-2255 p.
National Category
Biophysics Bioinformatics and Systems Biology Theoretical Chemistry
URN: urn:nbn:se:kth:diva-82588DOI: 10.1021/ci100266cISI: 000285559900017PubMedID: 21117677OAI: diva2:498399
Swedish e‐Science Research Center
QC 20120217Available from: 2012-02-12 Created: 2012-02-12 Last updated: 2012-05-22Bibliographically approved

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Lindahl, Erik
BiophysicsBioinformatics and Systems BiologyTheoretical Chemistry

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