3ZI0

Structure of Mycobacterium tuberculosis DXR in complex with a fosmidomycin analogue

3ZI0 の概要

• エントリーDOI: 10.2210/pdb3zi0/pdb
• 関連するPDBエントリー: 3ZHX 3ZHY 3ZHZ
• 分子名称: 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, [(1S)-1-(3,4-dichlorophenyl)-3-{hydroxy[2-(1H-1,2,4-triazol-1-ylmethyl)benzoyl]amino}propyl]phosphonic acid, MANGANESE (II) ION, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, rv2870c, doxp/mep pathway, tuberculosis, ispc
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 83739.93

構造登録者

Bjorkelid, C.,Jansson, A.M.,Bergfors, T.,Unge, T.,Mowbray, S.L.,Jones, T.A. (登録日: 2012-12-30, 公開日: 2013-10-09, 最終更新日: 2024-05-08)

主引用文献

Jansson, A.M.,Wieckowska, A.,Bjorkelid, C.,Yahiaoui, S.,Sooriyaarachchi, S.,Lindh, M.,Bergfors, T.,Dharavath, S.,Desroses, M.,Suresh, S.,Andaloussi, M.,Nikhil, R.,Sreevalli, S.,Srinivasa, B.R.,Larhed, M.,Jones, T.A.,Karlen, A.,Mowbray, S.L.
Dxr Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues.
J.Med.Chem., 56:6190-, 2013

PubMed Abstract: The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway, producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.

PubMed: 23819803
DOI: 10.1021/JM4006498

実験手法

X-RAY DIFFRACTION (1.9 Å)