3V93

unliganded structure of TcrPDEC1 catalytic domain

3V93 の概要

• エントリーDOI: 10.2210/pdb3v93/pdb
• 関連するPDBエントリー: 3V94
• 分子名称: Cyclic nucleotide specific phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: parasite, phosphodiesterases, hydrolase
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 303300.84

構造登録者

Wang, H.,Kunz, S.,Chen, G.,Seebeck, T.,Wan, Y.,Robinson, H.,Martinelli, S.,Ke, H. (登録日: 2011-12-23, 公開日: 2012-02-22, 最終更新日: 2024-02-28)

主引用文献

Wang, H.,Kunz, S.,Chen, G.,Seebeck, T.,Wan, Y.,Robinson, H.,Martinelli, S.,Ke, H.
Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors.
J.Biol.Chem., 287:11788-11797, 2012

PubMed Abstract: Trypanosoma cruzi phosphodiesterase C (TcrPDEC) is a potential new drug target for the treatment of Chagas disease but has not been well studied. This study reports the enzymatic properties of various kinetoplastid PDECs and the crystal structures of the unliganded TcrPDEC1 catalytic domain and its complex with an inhibitor. Mutations of PDEC during the course of evolution led to inactivation of PDEC in Trypanosoma brucei/Trypanosoma evansi/Trypanosoma congolense, whereas the enzyme is active in all other kinetoplastids. The TcrPDEC1 catalytic domain hydrolyzes both cAMP and cGMP with a K(m) of 23.8 μm and a k(cat) of 31 s(-1) for cAMP and a K(m) of 99.1 μm and a k(cat) of 17 s(-1) for cGMP, thus confirming its dual specificity. The crystal structures show that the N-terminal fragment wraps around the TcrPDEC catalytic domain and may thus regulate its enzymatic activity via direct interactions with the active site residues. A PDE5 selective inhibitor that has an IC(50) of 230 nm for TcrPDEC1 binds to TcrPDEC1 in an orientation opposite to that of sildenafil. This observation, together with the screen of the inhibitory potency of human PDE inhibitors against TcrPDEC, implies that the scaffold of some human PDE inhibitors might be used as the starting model for design of parasite PDE inhibitors. The structural study also identified a unique parasite pocket that neighbors the active site and may thus be valuable for the design of parasite-specific inhibitors.

PubMed: 22356915
DOI: 10.1074/jbc.M111.326777

実験手法

X-RAY DIFFRACTION (2 Å)