+検索条件
-Structure paper
タイトル | Structural bases of TRP channel TRPV6 allosteric modulation by 2-APB. |
---|---|
ジャーナル・号・ページ | Nat Commun, Vol. 9, Issue 1, Page 2465, Year 2018 |
掲載日 | 2018年6月25日 |
著者 | Appu K Singh / Kei Saotome / Luke L McGoldrick / Alexander I Sobolevsky / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:29941865 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 3.37 - 4.44 Å |
構造データ | EMDB-7825, PDB-6d7t: PDB-6d7o: PDB-6d7p: PDB-6d7q: PDB-6d7v: PDB-6d7x: |
化合物 | ChemComp-CA: ChemComp-FZ4: ChemComp-DTB: ChemComp-FYY: |
由来 |
|
キーワード | membrane protein/inhibitor (生体膜) / Ion channels (イオンチャネル) / transporter (運搬体タンパク質) / calcium channel (カルシウムチャネル) / epithelial calcium channel / MEMBRANE PROTEIN (膜タンパク質) / membrane protein-inhibitor complex (生体膜) |