EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

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	7824 6d7s EMDB-7824, PDB-6d7s: Cryo-EM structure of human TRPV6-Y467A in amphipols 手法: EM (単粒子) / 解像度: 4.34 Å 7825 6d7t EMDB-7825, PDB-6d7t: Cryo-EM structure of human TRPV6-Y467A in complex with 2-Aminoethoxydiphenyl borate (2-APB) 手法: EM (単粒子) / 解像度: 4.44 Å PDB-6d7o: Crystal Structure of Rat TRPV6* in complex with 2-Aminoethoxydiphenyl borate (2-APB) 手法: X-RAY DIFFRACTION / 解像度: 3.45 Å PDB-6d7p: Crystal Structure of Rat *TRPV6-Y466A 手法: X-RAY DIFFRACTION / 解像度: 3.37 Å PDB-6d7q: Crystal Structure of Rat TRPV6-Y466A* in complex with 2-Aminoethoxydiphenyl borate (2-APB) 手法: X-RAY DIFFRACTION / 解像度: 3.497 Å PDB-6d7v: Crystal Structure of Rat *TRPV6- in complex with brominated 2-Aminoethoxydiphenyl borate (2-APB-Br) 手法: X-RAY DIFFRACTION / 解像度: 4.3 Å PDB-6d7x: Crystal Structure of Rat TRPV6-Y466A-* in complex with brominated 2-Aminoethoxydiphenyl borate (2-APB-Br) 手法: X-RAY DIFFRACTION / 解像度: 3.6 Å
化合物	ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-FZ4: 2-aminoethyl diphenylborinate / 2-APB / ジフェニルボリン酸2-アミノエチル ChemComp-DTB: 6-(5-METHYL-2-OXO-IMIDAZOLIDIN-4-YL)-HEXANOIC ACID / デスチオビオチン ChemComp-FYY: 2-aminoethyl (4-bromophenyl)phenylborinate
由来	homo sapiens (ヒト) rattus norvegicus (ドブネズミ)
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)