7B16

TRPC4 in complex with inhibitor GFB-9289

7B16 の概要

• エントリーDOI: 10.2210/pdb7b16/pdb
• EMDBエントリー: 11957 11970 11979
• 分子名称: Transient receptor potential cation channel subfamily c member 4a, 5-chloranyl-4-(4-cyclohexyl-3-oxidanylidene-piperazin-1-yl)-1~{H}-pyridazin-6-one, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: ion channel, trpc4, inhibitor, membrane protein, transport protein
• 由来する生物種: Danio rerio (Zebrafish)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 424817.56

構造登録者

Vinayagam, D.,Quentin, D.,Sistel, O.,Merino, F.,Stabrin, M.,Hofnagel, O.,Ledeboer, M.W.,Malojcic, G.,Raunser, S. (登録日: 2020-11-23, 公開日: 2020-12-09, 最終更新日: 2024-05-01)

主引用文献

Vinayagam, D.,Quentin, D.,Yu-Strzelczyk, J.,Sitsel, O.,Merino, F.,Stabrin, M.,Hofnagel, O.,Yu, M.,Ledeboer, M.W.,Nagel, G.,Malojcic, G.,Raunser, S.
Structural basis of TRPC4 regulation by calmodulin and pharmacological agents.
Elife, 9:-, 2020

PubMed Abstract: Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin (CaM). Molecular details of both CaM and drug binding have remained elusive so far. Here, we report structures of TRPC4 in complex with three pyridazinone-based inhibitors and CaM. The structures reveal that all the inhibitors bind to the same cavity of the voltage-sensing-like domain and allow us to describe how structural changes from the ligand-binding site can be transmitted to the central ion-conducting pore of TRPC4. CaM binds to the rib helix of TRPC4, which results in the ordering of a previously disordered region, fixing the channel in its closed conformation. This represents a novel CaM-induced regulatory mechanism of canonical TRP channels.

PubMed: 33236980
DOI: 10.7554/eLife.60603

実験手法

ELECTRON MICROSCOPY (3.15 Å)