Inhibition versus Potentiation of Ligand-Gated Ion Channels Can Be Altered by a Single Mutation that Moves Ligands between Intra- and Intersubunit Sites
2013 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 21, no 8, 1307-1316 p.Article in journal (Refereed) Published
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.
Nicotinic Acetylcholine-Receptor, Molecular-Dynamics Simulations, Anesthetic Binding-Site, Transmembrane Domain, Gaba(A) Receptor, General-Anesthesia, Subunit Interfaces, Glycine Receptors, Structural Basis, Delta-Subunit
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:kth:diva-127751DOI: 10.1016/j.str.2013.06.018ISI: 000322927900007ScopusID: 2-s2.0-84881474053OAI: oai:DiVA.org:kth-127751DiVA: diva2:646347
FunderScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, European Research Council, 209825Swedish Research Council, 2010-491 2010-5107Swedish e‐Science Research Center
QC 201309092013-09-092013-09-052013-09-09Bibliographically approved