Abstract
Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. The TRP channel TRPV6 mediates calcium uptake in epithelia and its expression is dramatically increased in numerous types of cancer. TRPV6 inhibitors suppress tumor growth, but the molecular mechanism of inhibition remains unknown. Here, we present crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. 2-APB binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1–S4 transmembrane helix bundle. Comparing human wild-type and high-affinity mutant Y467A structures, we show that 2-APB induces TRPV6 channel closure by modulating protein–lipid interactions. Mutagenesis and functional analyses suggest that the identified 2-APB binding site might be present in other members of vanilloid subfamily TRP channels. Our findings reveal a mechanism of ion channel allosteric modulation that can be exploited for therapeutic design.
Highlights
Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction
A membrane-permeable compound 2-aminoethoxydiphenyl borate (2-APB), one of the few known small-molecule inhibitors of TRPV6, has been shown to attenuate tumor growth and invasiveness in human cancer cell lines in vitro26. 2-APB was initially characterized as an inhibitor of Ins(1,4,5)P3 receptor-induced Ca2+ release[28], but was later shown to modulate the functions of different ion channels, including calcium release-activated[29] and two-pore potassium[30] channels. 2-APB modulation of TRP channels[31], includes activation of TRPV1, TRPV2, TRPV3, TRPA1, and TRPM632–35 and inhibition of TRPM2, TRPM7, TRPC3, TRPC6, and TRPC736–38
We find that 2-APB induces TRPV6 channel closure by modulating protein–lipid interactions
Summary
Transient receptor potential (TRP) channels are involved in various physiological processes, including sensory transduction. We present crystal and cryo-EM structures of human and rat TRPV6 bound to 2-aminoethoxydiphenyl borate (2-APB), a TRPV6 inhibitor and modulator of numerous TRP channels. Mutagenesis and functional analyses suggest that the identified 2-APB binding site might be present in other members of vanilloid subfamily TRP channels. 1234567890():,; The transient receptor potential (TRP) ion channel superfamily comprises members that are involved in various physiological functions ranging from sensory transduction to calcium homeostasis[1]. A limited number of small-molecule[23,24,25,26] and peptide[27] inhibitors of TRPV6 have been identified as potential leads for cancer treatment, but advances in drug development are hampered by lack of knowledge about the possible molecular mechanisms of TRPV6 inhibition. Our proposed mechanism of TRPV6 inhibition by 2-APB, contributes to the general principles of TRP channel regulation by small hydrophobic molecules
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