4R5V

Structure of the m1 alanylaminopeptidase from malaria complexed with a hydroxamic acid-based inhibitor

4R5V の概要

• エントリーDOI: 10.2210/pdb4r5v/pdb
• 関連するPDBエントリー: 3EBG 4R5T 4R5X 4R6T 4R76 4R7M
• 分子名称: M1 family aminopeptidase, ZINC ION, N-{(1R)-2-(hydroxyamino)-2-oxo-1-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-2,2-dimethylpropanamide, ... (5 entities in total)
• 機能のキーワード: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum FcB1/Columbia
• 細胞内の位置: Cytoplasm: O96935
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 105118.54

構造登録者

Drinkwater, N.,Mcgowan, S. (登録日: 2014-08-22, 公開日: 2014-10-29, 最終更新日: 2023-09-20)

主引用文献

Mistry, S.N.,Drinkwater, N.,Ruggeri, C.,Sivaraman, K.K.,Loganathan, S.,Fletcher, S.,Drag, M.,Paiardini, A.,Avery, V.M.,Scammells, P.J.,McGowan, S.
Two-Pronged Attack: Dual Inhibition of Plasmodium falciparum M1 and M17 Metalloaminopeptidases by a Novel Series of Hydroxamic Acid-Based Inhibitors.
J.Med.Chem., 57:9168-9183, 2014

PubMed Abstract: Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.

PubMed: 25299353
DOI: 10.1021/jm501323a

実験手法

X-RAY DIFFRACTION (2.1 Å)