Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
- VIB-VUB Center for Structural Biology, Belgium
- KU Leuven, Belgium
Abstract
Cys-loop receptors or pentameric ligand-gated ion channels are mediators of electrochemical signaling throughout the animal kingdom. Because of their critical function in neurotransmission and high potential as drug targets, Cys-loop receptors from humans and closely related organisms have been thoroughly investigated, whereas molecular mechanisms of neurotransmission in invertebrates are less understood. When compared with vertebrates, the invertebrate genomes underwent a drastic expansion in the number of the nACh-like genes associated with receptors of unknown function. Understanding this diversity contributes to better insight into the evolution and possible functional divergence of these receptors. In this work, we studied orphan receptor Alpo4 from an extreme thermophile worm Alvinella pompejana. Sequence analysis points towards its remote relation to characterized nACh receptors. We solved the cryo-EM structure of the lophotrochozoan nACh-like receptor in which a CHAPS molecule is tightly bound to the orthosteric site. We show that the binding of CHAPS leads to extending of the loop C at the orthosteric site and a quaternary twist between extracellular and transmembrane domains. Both the ligand binding site and the channel pore reveal unique features. These include a conserved Trp residue in loop B of the ligand binding site which is flipped into an apparent self-liganded state in the apo structure. The ion pore of Alpo4 is tightly constricted by a ring of methionines near the extracellular entryway of the channel pore. Our data provide a structural basis for a functional understanding of Alpo4 and hints towards new strategies for designing specific channel modulators.
Data availability
The cryo-EM density maps and atomic models generated in this study have been deposited in the PDB and EMDB database under accession codes: 8BYI / EMDB-16326 (Alpo4CHAPS), 8BXF / EMDB- 16317 (Alpo4APO), 8BX5 / EMDB-16308 (Alpo4LMNG_APO), 8BXB / EMDB-16314 (Alpo4ACH), 8BKE / EMDB-16316 (Alpo4COMB), 8BKD / EMDB-16315 (Alpo4SER).
Article and author information
Author details
Funding
Fonds Wetenschappelijk Onderzoek (G0H5916N)
- Rouslan G Efremov
Fonds Wetenschappelijk Onderzoek (G054617N)
- Rouslan G Efremov
Fonds Wetenschappelijk Onderzoek (G0H5916N)
- Steven De Gieter
Fonds Wetenschappelijk Onderzoek (G0C1319N)
- Chris Ulens
Fonds Wetenschappelijk Onderzoek (G087921N)
- Chris Ulens
KU Leuven (C3/19/023)
- Chris Ulens
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marcel P Goldschen-Ohm, University of Texas at Austin, United States
Version history
- Preprint posted: January 6, 2023 (view preprint)
- Received: January 8, 2023
- Accepted: July 2, 2023
- Accepted Manuscript published: July 3, 2023 (version 1)
- Version of Record published: July 12, 2023 (version 2)
Copyright
© 2023, De Gieter 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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Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
eLife 12:e86029.
https://doi.org/10.7554/eLife.86029
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