Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site
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 d...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-01-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/51511 |
| _version_ | 1811202700415598592 |
|---|---|
| author | Marijke Brams Cedric Govaerts Kumiko Kambara Kerry L Price Radovan Spurny Anant Gharpure Els Pardon Genevieve L Evans Daniel Bertrand Sarah CR Lummis Ryan E Hibbs Jan Steyaert Chris Ulens |
| author_facet | Marijke Brams Cedric Govaerts Kumiko Kambara Kerry L Price Radovan Spurny Anant Gharpure Els Pardon Genevieve L Evans Daniel Bertrand Sarah CR Lummis Ryan E Hibbs Jan Steyaert Chris Ulens |
| author_sort | Marijke Brams |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:42:47Z |
| format | Article |
| id | doaj.art-342cb67467c141c1a4b0ebacf9821115 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:42:47Z |
| publishDate | 2020-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-342cb67467c141c1a4b0ebacf98211152022-12-22T03:51:16ZengeLife Sciences Publications LtdeLife2050-084X2020-01-01910.7554/eLife.51511Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule siteMarijke Brams0Cedric Govaerts1Kumiko Kambara2Kerry L Price3Radovan Spurny4Anant Gharpure5https://orcid.org/0000-0002-4458-359XEls Pardon6Genevieve L Evans7https://orcid.org/0000-0002-8612-9539Daniel Bertrand8Sarah CR Lummis9Ryan E Hibbs10Jan Steyaert11https://orcid.org/0000-0002-3825-874XChris Ulens12https://orcid.org/0000-0002-8202-5281Laboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, BelgiumLaboratory for the Structure and Function of Biological Membranes, Center for Structural Biology and Bioinformatics, Université libre de Bruxelles, Brussels, BelgiumHiQscreen, Geneva, SwitzerlandDepartment of Biochemistry, University of Cambridge, Cambridge, United KingdomLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, BelgiumDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United StatesStructural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, Brussels, BelgiumLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, BelgiumHiQscreen, Geneva, SwitzerlandDepartment of Biochemistry, University of Cambridge, Cambridge, United KingdomDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United StatesStructural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium; VIB-VUB Center for Structural Biology, VIB, Brussels, BelgiumLaboratory of Structural Neurobiology, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, BelgiumPentameric 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.https://elifesciences.org/articles/51511ligand-gated ion channelsstructural biologyallosteric modulation |
| spellingShingle | Marijke Brams Cedric Govaerts Kumiko Kambara Kerry L Price Radovan Spurny Anant Gharpure Els Pardon Genevieve L Evans Daniel Bertrand Sarah CR Lummis Ryan E Hibbs Jan Steyaert Chris Ulens Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site eLife ligand-gated ion channels structural biology allosteric modulation |
| title | Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site |
| title_full | Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site |
| title_fullStr | Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site |
| title_full_unstemmed | Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site |
| title_short | Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site |
| title_sort | modulation of the erwinia ligand gated ion channel elic and the 5 ht3 receptor via a common vestibule site |
| topic | ligand-gated ion channels structural biology allosteric modulation |
| url | https://elifesciences.org/articles/51511 |
| work_keys_str_mv | AT marijkebrams modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT cedricgovaerts modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT kumikokambara modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT kerrylprice modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT radovanspurny modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT anantgharpure modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT elspardon modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT genevievelevans modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT danielbertrand modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT sarahcrlummis modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT ryanehibbs modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT jansteyaert modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite AT chrisulens modulationoftheerwinialigandgatedionchannelelicandthe5ht3receptorviaacommonvestibulesite |