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Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor

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 thor...

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Autores principales: De Gieter, Steven, Gallagher, Casey I, Wijckmans, Eveline, Pasini, Diletta, Ulens, Chris, Efremov, Rouslan G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338036/
https://www.ncbi.nlm.nih.gov/pubmed/37395731
http://dx.doi.org/10.7554/eLife.86029
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author De Gieter, Steven
Gallagher, Casey I
Wijckmans, Eveline
Pasini, Diletta
Ulens, Chris
Efremov, Rouslan G
author_facet De Gieter, Steven
Gallagher, Casey I
Wijckmans, Eveline
Pasini, Diletta
Ulens, Chris
Efremov, Rouslan G
author_sort De Gieter, Steven
collection PubMed
description 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.
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spelling pubmed-103380362023-07-13 Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor De Gieter, Steven Gallagher, Casey I Wijckmans, Eveline Pasini, Diletta Ulens, Chris Efremov, Rouslan G eLife Structural Biology and Molecular Biophysics 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. eLife Sciences Publications, Ltd 2023-07-03 /pmc/articles/PMC10338036/ /pubmed/37395731 http://dx.doi.org/10.7554/eLife.86029 Text en © 2023, De Gieter et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
De Gieter, Steven
Gallagher, Casey I
Wijckmans, Eveline
Pasini, Diletta
Ulens, Chris
Efremov, Rouslan G
Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
title Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
title_full Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
title_fullStr Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
title_full_unstemmed Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
title_short Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor
title_sort sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate cys-loop receptor
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338036/
https://www.ncbi.nlm.nih.gov/pubmed/37395731
http://dx.doi.org/10.7554/eLife.86029
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