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Structural basis for channel conduction in the pump-like channelrhodopsin ChRmine
Open accessPublished version of a preprint
Abstract
ChRmine, a recently discovered pump-like cation-conducting channelrhodopsin, exhibits puzzling properties (large photocurrents, red-shifted spectrum, and extreme light sensitivity) that have created new opportunities in optogenetics. ChRmine and its homologs function as ion channels but, by primary sequence, more closely resemble ion pump rhodopsins; mechanisms for passive channel conduction in this family have remained mysterious. Here, we present the 2.0 Å resolution cryo-EM structure of ChRmine, revealing architectural features atypical for channelrhodopsins: trimeric assembly, a short transmembrane-helix 3, a twisting extracellular-loop 1, large vestibules within the monomer, and an opening at the trimer interface. We applied this structure to design three proteins (rsChRmine and hsChRmine, conferring further red-shifted and high-speed properties, respectively, and frChRmine, combining faster and more red-shifted performance) suitable for fundamental neuroscience opportunities. These results illuminate the conduction and gating of pump-like channelrhodopsins and point the way toward further structure-guided creation of channelrhodopsins for applications across biology.
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“while the AF2 model of the channelrhodopsin ChRmine captures its overall fold, the modeled N-terminal region and extracellular loops deviate from its experimental high-resolution cryogenic electron microscopy (cryo-EM) structure (Fig. 2f), likely due to ChRmine’s unique covalent Schiff base feature41”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [41]
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Research works printed but not linked: 1
- Kishi, 2021, Structural basis for channel conduction in the pump-like channelrhodopsin ChRmine, bioRxiv
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Metadata
- Authors
- Kishi, K. E., Kim, Y. S., Fukuda, M., Inoue, M., Kusakizako, T., Wang, P. Y., Ramakrishnan, C., Byrne, E. F. X., Thadhani, E., Paggi, J. M., Matsui, T. E., Yamashita, K., Nagata, T., Konno, M., Quirin, S., Lo, M., Benster, T., Uemura, T., Liu, K., Shibata, M., Nomura, N., Iwata, S., Nureki, O., Dror, R. O., Inoue, K., Deisseroth, K., & Kato, H. E.
- Affiliations
- Komaba Institute for Science, The University of Tokyo (JP)
- Stanford University (US)
- The University of Tokyo (JP)
- MRC Laboratory of Molecular Biology (GB)
- Japan Science and Technology Agency (JP)
- Kyoto University (JP)
- Kanazawa University (JP)
- The Institute for Solid State Physics, The University of Tokyo (JP)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Deisseroth, Karl
- Kato, Hideaki E.
- ORCID
- Kim, Yoon Seok
- Fukuda, Masahiro
- Inoue, Masatoshi
- Kusakizako, Tsukasa
- Wang, Peter Y.
- Ramakrishnan, Charu
- Byrne, Eamon F.X.
- Thadhani, Elina
- Paggi, Joseph M.
- Matsui, Toshiki E.
- Yamashita, Keitaro
- Nagata, Takashi
- Konno, Masae
- Quirin, Sean
- Liu, Kehong
- Shibata, Mikihiro
- Nomura, Norimichi
- Iwata, So
- Nureki, Osamu
- Dror, Ron O.
- Inoue, Keiichi
- Deisseroth, Karl
- Kato, Hideaki E.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 185
- Issue
- 4
- Pages
- 672-689.e23
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7612760
- OpenAlex
- W4221028201
- Cited by
- 149
- References
- 126
- Citations by year
- 2026: 19 · 2025: 40 · 2024: 23 · 2023: 39 · 2022: 24
- FWCI
- 13.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by)
- Funders
- Japan Agency for Medical Research and Development (JP18am0101079, JP20am0101115)
- UK Research and Innovation
- University of Tokyo
- Medical Research Council (MC_UP_A025_1012)
- Japan Society for the Promotion of Science (16H06294, 20K21122, 21H01771, 20K21383, 21H00247, 20K15754, 23K21092, 19H00923, JP21H01875, 19H05777, 20H05758)
- National Institute of Mental Health (R01MH075957, R37MH075957)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- channelrhodopsin, channel gating, cryo-EM structure, transmembrane helix 3, extracellular loop 1, optogenetics, protein engineering
- MeSH terms
- Channelrhodopsins, Animals, Female, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Phylogeny, Schiff Bases, Structure-Activity Relationship, Ion Channel Gating, Rats, Sprague-Dawley, Cryoelectron Microscopy, Mice, Rats, HEK293 Cells, Sf9 Cells, Optogenetics
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