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PreprintCited by 46Ion Channels and ReceptorsIon channel regulation and functionCalcium signaling and nucleotide metabolism

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Structure of human TRPM8 channel

Open access
Palchevskyi, Sergii, Czarnocki-Cieciura, Mariusz, Vistoli, Giulio, Gervasoni, Silvia, Nowak, Elżbieta, Beccari, Andrea, Nowotny, Marcin, Talarico, Carmine·2023·Communications Biology
DOI 10.21203/rs.3.rs-2487624/v1PMC PMC10587237

Preprint — published as 10.1038/s42003-023-05425-6

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Abstract

TRPM8 is a calcium ion channel that is activated by multiple factors, such as temperature, voltage, pressure, and osmolality. It is a therapeutic target for anticancer drug development, and its modulators can be utilized for several pathological conditions. Here, we present a cryo-electron microscopy structure of a human TRPM8 channel in the closed state that was solved at 2.7 Å resolution. Our structure comprises the most complete model of the N-terminal pre-melastatin homology region. We also visualized several ligands that are bound by the protein and modeled how the human channel interacts with icilin. Analyses of pore helices in available TRPM structures showed that all these structures can be grouped into different closed, desensitized and open state conformations based on the register of the pore helix S6 which positions particular amino acid residues at the channel constriction. Our structure is the first for the human TRPM8 protein and it is among the most complete and the highest resolution structures of any TRPM8 channel available.

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Metadata

Authors
Palchevskyi, S., Czarnocki-Cieciura, M., Vistoli, G., Gervasoni, S., Nowak, E., Beccari, A., Nowotny, M., & Talarico, C.
Affiliations
  • International Institute of Molecular and Cell Biology in Warsaw
  • Laboratory of Protein Structure, International Institute of Molecular and Cell Biology
  • University of Milan (IT)
  • University of Cagliari (IT)
  • International Institute of Molecular and Cell Biology (PL)
  • Dompé farmaceutici SpA
  • Dompé Farmaceutici S.p.A
Corresponding author
  • Nowotny, Marcin
  • Talarico, Carmine
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2023-02-10
Volume
6
Issue
1
Pages
1065-1065
ISSN
2399-3642 (ISSN-L)
DOI
10.21203/rs.3.rs-2487624/v1
PMC
PMC10587237
OpenAlex
W4387782156
Cited by
46
References
1
Citations by year
2026: 11 · 2025: 18 · 2024: 17
FWCI
8.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministero dello Sviluppo Economico (F/090033/01-03-04/X36)
  • Międzynarodowy Instytut Biologii Molekularnej i Komórkowej w Warszawie
  • Institute of Molecular and Cell Biology
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
TRPM8, closed state, icilin, channel gating, protein-lipid interactions, channel desensitization, temperature sensing, anticancer drug targets
MeSH terms
Humans, Membrane Proteins, Temperature, Cryoelectron Microscopy, TRPM Cation Channels

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