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.
Reviewing Editor
- Cynthia M Czajkowski, University of Wisconsin, Madison, United States
Version history
- Received: August 30, 2019
- Accepted: January 27, 2020
- Accepted Manuscript published: January 28, 2020 (version 1)
- Version of Record published: February 12, 2020 (version 2)
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
Further reading
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- Neuroscience
Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or ‘iconic’ memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these time scales. Here, we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.
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- Neuroscience
Our ability to recall details from a remembered image depends on a single mechanism that is engaged from the very moment the image disappears from view.
