Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment
Abstract GLIC, a proton-activated prokaryotic ligand-gated ion channel, served as a model system for understanding the eukaryotic counterparts due to their structural and functional similarities. Despite extensive studies conducted on GLIC, the molecular mechanism of channel gating in the lipid envi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-47370-w |
| _version_ | 1797219722972889088 |
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| author | Nikhil Bharambe Zhuowen Li David Seiferth Asha Manikkoth Balakrishna Philip C. Biggin Sandip Basak |
| author_facet | Nikhil Bharambe Zhuowen Li David Seiferth Asha Manikkoth Balakrishna Philip C. Biggin Sandip Basak |
| author_sort | Nikhil Bharambe |
| collection | DOAJ |
| description | Abstract GLIC, a proton-activated prokaryotic ligand-gated ion channel, served as a model system for understanding the eukaryotic counterparts due to their structural and functional similarities. Despite extensive studies conducted on GLIC, the molecular mechanism of channel gating in the lipid environment requires further investigation. Here, we present the cryo-EM structures of nanodisc-reconstituted GLIC at neutral and acidic pH in the resolution range of 2.6 – 3.4 Å. In our apo state at pH 7.5, the extracellular domain (ECD) displays conformational variations compared to the existing apo structures. At pH 4.0, three distinct conformational states (C1, C2 and O states) are identified. The protonated structures exhibit a compacted and counter-clockwise rotated ECD compared with our apo state. A gradual widening of the pore in the TMD is observed upon reducing the pH, with the widest pore in O state, accompanied by several layers of water pentagons. The pore radius and molecular dynamics (MD) simulations suggest that the O state represents an open conductive state. We also observe state-dependent interactions between several lipids and proteins that may be involved in the regulation of channel gating. Our results provide comprehensive insights into the importance of lipids impact on gating. |
| first_indexed | 2024-04-24T12:38:10Z |
| format | Article |
| id | doaj.art-3bd6a03aed1f435eb408bda9619f8fd6 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:38:10Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-3bd6a03aed1f435eb408bda9619f8fd62024-04-07T11:24:03ZengNature PortfolioNature Communications2041-17232024-04-0115111610.1038/s41467-024-47370-wCryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environmentNikhil Bharambe0Zhuowen Li1David Seiferth2Asha Manikkoth Balakrishna3Philip C. Biggin4Sandip Basak5School of Biological Sciences, Nanyang Technological UniversitySchool of Biological Sciences, Nanyang Technological UniversityStructural Bioinformatics and Computational Biochemistry, Department of Biochemistry, University of OxfordSchool of Biological Sciences, Nanyang Technological UniversityStructural Bioinformatics and Computational Biochemistry, Department of Biochemistry, University of OxfordSchool of Biological Sciences, Nanyang Technological UniversityAbstract GLIC, a proton-activated prokaryotic ligand-gated ion channel, served as a model system for understanding the eukaryotic counterparts due to their structural and functional similarities. Despite extensive studies conducted on GLIC, the molecular mechanism of channel gating in the lipid environment requires further investigation. Here, we present the cryo-EM structures of nanodisc-reconstituted GLIC at neutral and acidic pH in the resolution range of 2.6 – 3.4 Å. In our apo state at pH 7.5, the extracellular domain (ECD) displays conformational variations compared to the existing apo structures. At pH 4.0, three distinct conformational states (C1, C2 and O states) are identified. The protonated structures exhibit a compacted and counter-clockwise rotated ECD compared with our apo state. A gradual widening of the pore in the TMD is observed upon reducing the pH, with the widest pore in O state, accompanied by several layers of water pentagons. The pore radius and molecular dynamics (MD) simulations suggest that the O state represents an open conductive state. We also observe state-dependent interactions between several lipids and proteins that may be involved in the regulation of channel gating. Our results provide comprehensive insights into the importance of lipids impact on gating.https://doi.org/10.1038/s41467-024-47370-w |
| spellingShingle | Nikhil Bharambe Zhuowen Li David Seiferth Asha Manikkoth Balakrishna Philip C. Biggin Sandip Basak Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment Nature Communications |
| title | Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment |
| title_full | Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment |
| title_fullStr | Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment |
| title_full_unstemmed | Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment |
| title_short | Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment |
| title_sort | cryo em structures of prokaryotic ligand gated ion channel glic provide insights into gating in a lipid environment |
| url | https://doi.org/10.1038/s41467-024-47370-w |
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