- PDB-7k4e: Cryo-EM structure of human TRPV6 in complex with (4- phenylcycloh... -
+
データを開く
IDまたはキーワード:
読み込み中...
-
基本情報
登録情報
データベース: PDB / ID: 7k4e
タイトル
Cryo-EM structure of human TRPV6 in complex with (4- phenylcyclohexyl)piperazine inhibitor 30
要素
Transient receptor potential cation channel subfamily V member 6
キーワード
MEMBRANE PROTEIN/INHIBITOR / TRPV6 / ion channel / inhibitor / MEMBRANE PROTEIN / MEMBRANE PROTEIN-INHIBITOR complex
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 region circular profile. / Ankyrin repeat 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 region circular profile. / Ankyrin repeat 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
Chem-VUJ / 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 Science Foundation (NSF, United States)
1818086
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM103310
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
P30 GM124165
米国
引用
ジャーナル: Sci Adv / 年: 2020 タイトル: Inactivation-mimicking block of the epithelial calcium channel TRPV6. 著者: Rajesh Bhardwaj / Sonja Lindinger / Arthur Neuberger / Kirill D Nadezhdin / Appu K Singh / Micael R Cunha / Isabella Derler / Gergely Gyimesi / Jean-Louis Reymond / Matthias A Hediger / ...著者: Rajesh Bhardwaj / Sonja Lindinger / Arthur Neuberger / Kirill D Nadezhdin / Appu K Singh / Micael R Cunha / Isabella Derler / Gergely Gyimesi / Jean-Louis Reymond / Matthias A Hediger / Christoph Romanin / Alexander I Sobolevsky / 要旨: Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of ...Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of selective nanomolar-affinity TRPV6 inhibition by (4-phenylcyclohexyl)piperazine derivatives (PCHPDs). We use x-ray crystallography and cryo-electron microscopy to solve the inhibitor-bound structures of TRPV6 and identify two types of inhibitor binding sites in the transmembrane region: (i) modulatory sites between the S1-S4 and pore domains normally occupied by lipids and (ii) the main site in the ion channel pore. Our structural data combined with mutagenesis, functional and computational approaches suggest that PCHPDs plug the open pore of TRPV6 and convert the channel into a nonconducting state, mimicking the action of calmodulin, which causes inactivation of TRPV6 channels under physiological conditions. This mechanism of inhibition explains the high selectivity and potency of PCHPDs and opens up unexplored avenues for the design of future-generation biomimetic drugs.