3zhz

Structure of Mycobacterium tuberculosis DXR in complex with a fosmidomycin analogue

spinqualitylabelsall models 3zhz, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3zhz is a 2 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FM7 Related: 3zhx, 3zhy, 3zi0 Activity: 1-deoxy-D-xylulose-5-phosphate reductoisomerase, with EC number 1.1.1.267 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DXR_MYCTU] Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) (By similarity). Publication Abstract from PubMed 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 Calpha 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. DXR inhibition by potent mono- and disubstituted fosmidomycin analogues.,Jansson AM, 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 BR, Larhed M, Jones TA, Karlen A, Mowbray SL J Med Chem. 2013 Aug 8;56(15):6190-9. doi: 10.1021/jm4006498. Epub 2013 Jul 17. PMID:23819803 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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