Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB

• Published in: Nature communications 2018-06, Vol.9 (1), p.2465-11, Article 2465
• Main Authors: Singh, Appu K., Saotome, Kei, McGoldrick, Luke L., Sobolevsky, Alexander I.
• Format: Article
• Language: English
• Subjects: 101/28; 13/106; 631/535/1258/1259; 631/535/1266/1265; 631/57/2283; 82/16; 82/83; Allosteric properties; Animals; Binding sites; Binding Sites - genetics; Boron Compounds - chemistry; Calcium; Calcium - metabolism; Calcium Channels - metabolism; Calcium influx; Cancer; Crystal structure; Crystallography, X-Ray; HEK293 Cells; Humanities and Social Sciences; Humans; Ion channels; Lipid Metabolism - physiology; Modulation; Molecular chains; multidisciplinary; Mutagenesis; Neoplasms - pathology; Protein Structure, Secondary; Proteins; Rats; Science; Science (multidisciplinary); Sensory transduction; Transient receptor potential proteins; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04828-y

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. The transient receptor potential channel TRPV6 mediates calcium uptake in epithelia and its expression is increased in several cancer types. Here, authors present structures of TRPV6 bound to 2-APB, a TRPV6 inhibitor, and show that 2-APB induces TRPV6 channel closure by modulating protein–lipid interactions.