The locking mechanism of human TRPV6 inhibition by intracellular magnesium.

ABSTRACT: TRPV6 is a member of the vanilloid subfamily of transient receptor potential channels, which serves as the master regulator of Ca²⁺ homeostasis. TRPV6 functions as a constitutively active Ca²⁺ 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 Mg²⁺. Mg²⁺ appears to bind to four, one per subunit, sites around the intracellular entrance to

SUBMITTER: Neuberger A 

PROVIDER: S-EPMC12592368 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature