9nq9
Magnesium ions-bound closed-state cryo-EM structure of human TRPV6 in cNW11 nanodiscs
Structural highlights
FunctionTRPV6_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 PubMedTRPV6 is a member of the vanilloid subfamily of transient receptor potential channels, which serves as the master regulator of Ca(2+) homeostasis. TRPV6 functions as a constitutively active Ca(2+) channel, and emerging evidence indicates that its overactivity underpins the progression of several human diseases, including cancer. Hence, there is a pressing need to identify TRPV6 inhibitors in conjunction with a deep mechanistic understanding of their effects on the channel activity. Here we combine cryo-electron microscopy, mutagenesis, electrophysiology and molecular dynamics modeling to decipher the molecular mechanism of TRPV6 inhibition by intracellular Mg(2+). Mg(2+) appears to bind to four, one per subunit, sites around the intracellular entrance to the TRPV6 channel pore, contributed by the negatively charged residues, D489 in the transmembrane helix S5 and D580 in S6. When bound to the D489-D580 site, Mg(2+) prevents the alpha-to-pi transition in the middle of S6 that accompanies channel opening, thus maintaining S6 entirely alpha-helical, locking the channel in the closed state and inhibiting TRPV6-mediated currents. Further exploration of this inhibitory mechanism may help to develop future strategies for the treatment of TRPV6-associated diseases. The locking mechanism of human TRPV6 inhibition by intracellular magnesium.,Neuberger A, Shalygin A, Veretenenko II, Trofimov YA, Gudermann T, Chubanov V, Efremov RG, Sobolevsky AI Nat Commun. 2025 Nov 6;16(1):9826. doi: 10.1038/s41467-025-65919-1. PMID:41198662[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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