6RFW

Crystal structure of T. brucei PDE-B1 catalytic domain with inhibitor NPD-1039

6RFW の概要

• エントリーDOI: 10.2210/pdb6rfw/pdb
• 関連するPDBエントリー: 6GXQ 6HWO 6RB6 6RCW 6RFN
• 分子名称: Phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (8 entities in total)
• 機能のキーワード: parasitic phosphodiesterase, hydrolase, african trypanosomiasis, sleeping sickness
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 82959.82

構造登録者

Singh, A.K.,Brown, D.G. (登録日: 2019-04-16, 公開日: 2019-07-24, 最終更新日: 2024-01-24)

主引用文献

de Heuvel, E.,Singh, A.K.,Boronat, P.,Kooistra, A.J.,van der Meer, T.,Sadek, P.,Blaazer, A.R.,Shaner, N.C.,Bindels, D.S.,Caljon, G.,Maes, L.,Sterk, G.J.,Siderius, M.,Oberholzer, M.,de Esch, I.J.P.,Brown, D.G.,Leurs, R.
Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2).
Bioorg.Med.Chem., 27:4013-4029, 2019

PubMed Abstract: Inhibitors against Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and B2 (TbrPDEB2) have gained interest as new treatments for human African trypanosomiasis. The recently reported alkynamide tetrahydrophthalazinones, which show submicromolar activities against TbrPDEB1 and anti-T. brucei activity, have been used as starting point for the discovery of new TbrPDEB1 inhibitors. Structure-based design indicated that the alkynamide-nitrogen atom can be readily decorated, leading to the discovery of 37, a potent TbrPDEB1 inhibitor with submicromolar activities against T. brucei parasites. Furthermore, 37 is more potent against TbrPDEB1 than hPDE4 and shows no cytotoxicity on human MRC-5 cells. The crystal structures of the catalytic domain of TbrPDEB1 co-crystalized with several different alkynamides show a bidentate interaction with key-residue Gln874, but no interaction with the parasite-specific P-pocket, despite being (uniquely) a more potent inhibitor for the parasite PDE. Incubation of blood stream form trypanosomes by 37 increases intracellular cAMP levels and results in the distortion of the cell cycle and cell death, validating phosphodiesterase inhibition as mode of action.

PubMed: 31378593
DOI: 10.1016/j.bmc.2019.06.026

実験手法

X-RAY DIFFRACTION (2.183 Å)