3ZHY

Structure of Mycobacterium tuberculosis DXR in complex with a di- substituted fosmidomycin analogue

Summary for 3ZHY

• Entry DOI: 10.2210/pdb3zhy/pdb
• Related: 3ZHX 3ZHZ 3ZI0
• Descriptor: 1-DEOXY-D-XYLULOSE 5-PHOSPHATE REDUCTOISOMERASE, MANGANESE (II) ION, [(1S)-1-(3,4-dichlorophenyl)-3-[oxidanyl(phenylcarbonyl)amino]propyl]phosphonic acid, ... (5 entities in total)
• Functional Keywords: oxidoreductase, rv2870c, doxp/mep pathway, ispc
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 2
• Total formula weight: 85608.82

Authors

Bjorkelid, C.,Jansson, A.M.,Bergfors, T.,Unge, T.,Mowbray, S.L.,Jones, T.A. (deposition date: 2012-12-30, release date: 2013-10-09, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)