ArticleNature communications2023
Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Open-channel block of human TRPV6 by polyamine spermine.Nature communications · 2026Article
- The locking mechanism of human TRPV6 inhibition by intracellular magnesium.Nature communications · 2025Article
- Asymmetric gating of a homopentameric ion channel GLIC revealed by cryo-EM.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Forty sites of TRP channel regulation.Current opinion in chemical biology · 2025Review
- Structure-function analyses of human TRPV6 ancestral and derived haplotypes.Structure (London, England : 1993) · 2025Article
- Recent advances on the structure and the function relationships of the TRPV4 ion channel.Channels (Austin, Tex.) · 2024Review
- Dynamic molecular portraits of ion-conducting pores characterize functional states of TRPV channels.Communications chemistry · 2024Article
- Effect of Tempeh and Daidzein on Calcium Status, Calcium Transporters, and Bone Metabolism Biomarkers in Ovariectomized Rats.Nutrients · 2024Article
- Role of TRP Channels in Metabolism-Related Diseases.International journal of molecular sciences · 2024Review
- Bidirectional Allosteric Coupling between PIPInternational journal of molecular sciences · 2024Article
- Molecular pharmacology of the onco-TRP channel TRPV6.Channels (Austin, Tex.) · 2023Review
- Pentameric TRPV3: An artifact or a clue to channel function?Cell calcium · 2023Article
- Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin.Nature communications · 2023Article
- Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. While significant effort has been invested in the development of synthetic TRPV6 inhibitors, natural channel blockers have been largely neglected. Here we report the structure of human TRPV6 in complex with the plant-derived phytoestrogen genistein, extracted from Styphnolobium japonicum, that was shown to inhibit cell invasion and metastasis in cancer clinical trials. Despite the pharmacological value, the molecular mechanism of TRPV6 inhibition by genistein has remained enigmatic. We use cryo-EM combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to show that genistein binds in the intracellular half of the TRPV6 pore and acts as an ion channel blocker and gating modifier. Genistein binding to the open channel causes pore closure and a two-fold symmetrical conformational rearrangement in the S4-S5 and S6-TRP helix regions. The unprecedented mechanism of TRPV6 inhibition by genistein uncovers new possibilities in structure-based drug design.
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