Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site
- KU Leuven, Belgium
- Université libre de Bruxelles, Belgium
- HiQScreen, Switzerland
- University of Cambridge, United Kingdom
- University of Texas Southwestern Medical Center, United States
- VIB-VUB, Belgium
Abstract
Pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling in the nervous system. Allosteric modulators bind to sites that are remote from the neurotransmitter binding site, but modify coupling of ligand binding to channel opening. In this study, we developed nanobodies (single domain antibodies), which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote (Erwinia) channel ELIC bound either to a positive or a negative allosteric modulator. The allosteric nanobody binding sites partially overlap with those of small molecule modulators, including a vestibule binding site that is not accessible in some pLGICs. Using mutagenesis, we extrapolate the functional importance of the vestibule binding site to the human 5-HT3 receptor, suggesting a common mechanism of modulation in this protein and ELIC. Thus we identify key elements of allosteric binding sites, and extend drug design possibilities in pLGICs with an accessible vestibule site.
Data availability
Atomic coordinates and structure factors have been deposited with the Protein Data Bank under accession numbers 6SSI for the ELIC+PAM-Nb structure and 6SSP for the ELIC+NAM-Nb structure. The raw X-ray diffraction images for both data sets have been deposited on datadryad.org under accession number doi:10.5061/dryad.pv4097s.
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Data from: Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule siteDryad Digital Repository, doi:10.5061/dryad.pv4097s.
Article and author information
Author details
Funding
SBO/IWT (1200261)
- Jan Steyaert
- Chris Ulens
FWO-Vlaanderen (G.0762.13)
- Jan Steyaert
- Chris Ulens
KU Leuven (OT/13/095)
- Chris Ulens
KU Leuven (C32/16/035)
- Chris Ulens
KU Leuven (C14/17/093)
- Chris Ulens
INSTRUCT-ERIC
- Jan Steyaert
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Brams et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site
eLife 9:e51511.
https://doi.org/10.7554/eLife.51511
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