| Structural highlights
Function
TRPV6_HUMAN Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine (PubMed:11097838, PubMed:11278579, PubMed:11248124 PubMed:15184369, PubMed:23612980). Important for normal Ca(2+) ion homeostasis in the body, including bone and skin (By similarity). The channel is activated by low internal calcium level, probably including intracellular calcium store depletion, and the current exhibits an inward rectification (PubMed:15184369). Inactivation includes both a rapid Ca(2+)-dependent and a slower Ca(2+)-calmodulin-dependent mechanism; the latter may be regulated by phosphorylation. In vitro, is slowly inhibited by Mg(2+) in a voltage-independent manner. Heteromeric assembly with TRPV5 seems to modify channel properties. TRPV5-TRPV6 heteromultimeric concatemers exhibit voltage-dependent gating.[UniProtKB:Q91WD2][1] [2] [3] [4] [5]
Publication Abstract from PubMed
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.
Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein.,Neuberger A, Trofimov YA, Yelshanskaya MV, Nadezhdin KD, Krylov NA, Efremov RG, Sobolevsky AI Nat Commun. 2023 May 9;14(1):2659. doi: 10.1038/s41467-023-38352-5. PMID:37160865[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. Human calcium transport protein CaT1. Biochem Biophys Res Commun. 2000 Nov 19;278(2):326-32. doi:, 10.1006/bbrc.2000.3716. PMID:11097838 doi:http://dx.doi.org/10.1006/bbrc.2000.3716
- ↑ Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5. doi: 10.1073/pnas.051511398. PMID:11248124 doi:http://dx.doi.org/10.1073/pnas.051511398
- ↑ Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. Expression of CaT-like, a novel calcium-selective channel, correlates with the malignancy of prostate cancer. J Biol Chem. 2001 Jun 1;276(22):19461-8. doi: 10.1074/jbc.M009895200. Epub 2001, Feb 2. PMID:11278579 doi:http://dx.doi.org/10.1074/jbc.M009895200
- ↑ Bodding M, Flockerzi V. Ca2+ dependence of the Ca2+-selective TRPV6 channel. J Biol Chem. 2004 Aug 27;279(35):36546-52. doi: 10.1074/jbc.M404679200. Epub 2004, Jun 7. PMID:15184369 doi:http://dx.doi.org/10.1074/jbc.M404679200
- ↑ Fecher-Trost C, Wissenbach U, Beck A, Schalkowsky P, Stoerger C, Doerr J, Dembek A, Simon-Thomas M, Weber A, Wollenberg P, Ruppert T, Middendorff R, Maurer HH, Flockerzi V. The in vivo TRPV6 protein starts at a non-AUG triplet, decoded as methionine, upstream of canonical initiation at AUG. J Biol Chem. 2013 Jun 7;288(23):16629-44. doi: 10.1074/jbc.M113.469726. Epub 2013, Apr 23. PMID:23612980 doi:http://dx.doi.org/10.1074/jbc.M113.469726
- ↑ Neuberger A, Trofimov YA, Yelshanskaya MV, Nadezhdin KD, Krylov NA, Efremov RG, Sobolevsky AI. Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Nat Commun. 2023 May 9;14(1):2659. PMID:37160865 doi:10.1038/s41467-023-38352-5
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