Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-8354-0253
Show others and affiliations
2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 43, E6696-E6703 p.Article in journal (Refereed) Published
Abstract [en]

Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the beta 8-beta 9 loop in the extracellular ligand-binding domain. The beta 8-beta 9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the beta 8-beta 9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors.

Place, publisher, year, edition, pages
National Academy of Sciences , 2016. Vol. 113, no 43, E6696-E6703 p.
Keyword [en]
ligand-gated ion channel, X-ray crystallography, allosteric modulation, Cys-loop receptor, nicotinic acetylcholine receptor
National Category
Other Engineering and Technologies
Identifiers
URN: urn:nbn:se:kth:diva-196603DOI: 10.1073/pnas.1603101113ISI: 000386087100020PubMedID: 27791038ScopusID: 2-s2.0-84992395900OAI: oai:DiVA.org:kth-196603DiVA: diva2:1051507
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20161202

Available from: 2016-12-02 Created: 2016-11-17 Last updated: 2017-02-28Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMedScopus

Search in DiVA

By author/editor
Yoluk, ÖzgeAndersson, MagnusLindahl, Erik
By organisation
Theoretical & Computational BiophysicsScience for Life Laboratory, SciLifeLab
In the same journal
Proceedings of the National Academy of Sciences of the United States of America
Other Engineering and Technologies

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 11 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf