Inhibition versus Potentiation of Ligand-Gated Ion Channels Can Be Altered by a Single Mutation that Moves Ligands between Intra- and Intersubunit Sites

Brömstrup, TorbenStockholms universitet,KTH,Science for Life Laboratory, SciLifeLab,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab) (author)

QC 20130909
AuthorCount:5;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
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.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
NATURVETENSKAP Biologi Cellbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Cell Biology hsv//eng
Nicotinic Acetylcholine-Receptor
Molecular-Dynamics Simulations
Anesthetic Binding-Site
Transmembrane Domain
Gaba(A) Receptor
General-Anesthesia
Subunit Interfaces
Glycine Receptors
Structural Basis
Delta-Subunit

Howard, Rebecca J. (author)
Trudell, James R. (author)
Harris, R. Adron (author)
Lindahl, ErikStockholms universitet,KTH,Beräkningsbiofysik,Science for Life Laboratory, SciLifeLab,Institutionen för biokemi och biofysik,Science for Life Laboratory (SciLifeLab)(Swepub:su)erlin (author)
KTHScience for Life Laboratory, SciLifeLab (creator_code:org_t)

By the author/editor: Brömstrup, Torbe ...; Howard, Rebecca ...; Trudell, James R ...; Harris, R. Adron; Lindahl, Erik

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Cell Biology

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