6D7O

Crystal Structure of Rat TRPV6* in complex with 2-Aminoethoxydiphenyl borate (2-APB)

6D7O の概要

• エントリーDOI: 10.2210/pdb6d7o/pdb
• 分子名称: Transient receptor potential cation channel subfamily V member 6, CALCIUM ION, 2-aminoethyl diphenylborinate, ... (4 entities in total)
• 機能のキーワード: ion channels, transporter, calcium channel, epithelial calcium channel, membrane protein, membrane protein-inhibitor complex, membrane protein/inhibitor
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 77612.93

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: 2023-10-04)

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

X-RAY DIFFRACTION (3.45 Å)