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Inhibition versus Potentiation of Ligand-Gated Ion Channels Can Be Altered by a Single Mutation that Moves Ligands between Intra- and Intersubunit Sites
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
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2013 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 21, no 8, 1307-1316 p.Article in journal (Refereed) Published
Abstract [en]

Pentameric ligand-gated ion channels (pLGICs) are similar in structure but either inhibited or potentiated by alcohols and anesthetics. This dual modulation has previously not been understood, but the determination of X-ray structures of prokaryotic GLIC provides an ideal model system. Here, we show that a single-site mutation at the F14' site in the GLIC transmembrane domain turns desflurane and chloroform from inhibitors to potentiators, and that this is explained by competing allosteric sites. The F14'A mutation opens an intersubunit site lined by N239 (15'), 1240 (16'), and Y263. Free energy calculations confirm this site is the preferred binding location for desflurane and chloroform in GLIC F14'A. In contrast, both anesthetics prefer an intrasubunit site in wild-type GLIC. Modulation is therefore the net effect of competitive binding between the intersubunit potentiating site and an intrasubunit inhibitory site. This provides direct evidence for a dual-site model of allosteric regulation of pLGICs.

Place, publisher, year, edition, pages
2013. Vol. 21, no 8, 1307-1316 p.
National Category
Biochemistry and Molecular Biology Cell Biology
URN: urn:nbn:se:su:diva-93573DOI: 10.1016/j.str.2013.06.018ISI: 000322927900007OAI: diva2:647444


Fundin Agencies:

European Research Council  209825;  Foundation for Strategic Research ;  Swedish Research Council  2010-491,  2010-5107;  Swedish e-Science Research Center;   National Institutes of Health/National Institutes on Alcohol Abuse and Alcoholism  T32 AA007471,  R01 AA06399,  R01 AA013378 

Available from: 2013-09-11 Created: 2013-09-10 Last updated: 2013-09-11Bibliographically approved

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Lindahl, Erik
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Department of Biochemistry and BiophysicsScience for Life Laboratory (SciLifeLab)
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