6D7S

Cryo-EM structure of human TRPV6-Y467A in amphipols

6D7S の概要

• エントリーDOI: 10.2210/pdb6d7s/pdb
• EMDBエントリー: 7824
• 分子名称: Transient receptor potential cation channel subfamily V member 6 (1 entity in total)
• 機能のキーワード: ion channels, transporter, calcium channel, epithelial calcium channel, membrane protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 340307.44

構造登録者

Singh, A.K.,Saotome, K.,McGoldrick, L.L.,Sobolevsky, A.I. (登録日: 2018-04-25, 公開日: 2018-07-18, 最終更新日: 2025-05-28)

主引用文献

Singh, A.K.,Saotome, K.,McGoldrick, L.L.,Sobolevsky, A.I.
Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB.
Nat Commun, 9:2465-2465, 2018

PubMed 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.

PubMed: 29941865
DOI: 10.1038/s41467-018-04828-y

実験手法

ELECTRON MICROSCOPY (4.34 Å)