8FOB
Cryo-EM structure of human TRPV6 in the open state
Summary for 8FOB
| Entry DOI | 10.2210/pdb8fob/pdb |
| Related | 8FOA |
| EMDB information | 29343 29344 |
| Descriptor | Transient receptor potential cation channel subfamily V member 6, CHOLESTEROL HEMISUCCINATE, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (6 entities in total) |
| Functional Keywords | transient receptor potential v family member 6, trp, human, channel, apo state, open, trpv6, trp channels, cancer, oncochannel, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 363562.79 |
| Authors | Neuberger, A.,Yelshanskaya, M.V.,Nadezhdin, K.D.,Sobolevsky, A.I. (deposition date: 2022-12-30, release date: 2023-05-24, Last modification date: 2024-06-19) |
| Primary citation | Neuberger, A.,Trofimov, Y.A.,Yelshanskaya, M.V.,Nadezhdin, K.D.,Krylov, N.A.,Efremov, R.G.,Sobolevsky, A.I. Structural mechanism of human oncochannel TRPV6 inhibition by the natural phytoestrogen genistein. Nat Commun, 14:2659-2659, 2023 Cited by PubMed 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. PubMed: 37160865DOI: 10.1038/s41467-023-38352-5 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.71 Å) |
Structure validation
Download full validation report
