- PDB-8sp8: Human TRP channel TRPV6 in cNW30 nanodiscs inhibited by tetrahydr... -
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基本情報
登録情報
データベース: PDB / ID: 8sp8
タイトル
Human TRP channel TRPV6 in cNW30 nanodiscs inhibited by tetrahydrocannabivarin (THCV)
要素
Transient receptor potential cation channel subfamily V member 6
キーワード
MEMBRANE PROTEIN / phyto-cannabinoid / phytocannabinoid / cannabindoid / tetrahydrocannabivarin / THCV / transient receptor potential V family member 6 / TRP / human / channel / closed / TRPV6 / TRP channels / cancer / oncochannel / cNW30 / nanodiscs / circularized nanodiscs / nanodisc / vanilloid
機能・相同性
機能・相同性情報
parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport ...parathyroid hormone secretion / regulation of calcium ion-dependent exocytosis / TRP channels / calcium ion import across plasma membrane / calcium ion homeostasis / calcium channel complex / calcium ion transmembrane transport / calcium channel activity / response to calcium ion / calcium ion transport / calmodulin binding / identical protein binding / metal ion binding / plasma membrane 類似検索 - 分子機能
Transient receptor potential cation channel subfamily V member 6 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential cation channel subfamily V member 6 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein 類似検索 - ドメイン・相同性
Tetrahydrocannabivarin / Chem-POV / CHOLESTEROL HEMISUCCINATE / Transient receptor potential cation channel subfamily V member 6 類似検索 - 構成要素
National Institutes of Health/National Cancer Institute (NIH/NCI)
R01 CA206573
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01 NS083660
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01 NS107253
米国
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)
R01 AR078814
米国
German Research Foundation (DFG)
464295817
ドイツ
引用
ジャーナル: Nat Commun / 年: 2023 タイトル: Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin. 著者: Arthur Neuberger / Yury A Trofimov / Maria V Yelshanskaya / Jeffrey Khau / Kirill D Nadezhdin / Lena S Khosrof / Nikolay A Krylov / Roman G Efremov / Alexander I Sobolevsky / 要旨: The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of ...The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.
生物種: Homo sapiens (ヒト) / 細胞: Human embryonic kidney 293 / プラスミド: pEG BacMam
緩衝液
pH: 8
緩衝液成分
ID
濃度
名称
式
Buffer-ID
1
150mM
sodiumchloride
NaCl
1
2
20mM
tris(hydroxymethyl)aminomethane
1
3
1mM
beta-Mercaptoethanol
1
4
0.114mM
tetrahydrocannabivarin
1
試料
濃度: 2.58 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: tetrameric oncochannel, human TRP channel, hTRPV6, in cNW30 lipid nanodiscs and soybean lipids in complex with and inhibited by the phytocannabinoid tetrahydrocannabivarin (THCV)