4a03

Crystal Structure of Mycobacterium tuberculosis DXR in complex with the antibiotic FR900098 and cofactor NADPH

spinqualitylabelsall models 4a03, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4a03 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.65Å Ligands: F98, GOL, MN, NDP 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 A number of pathogens, including the causative agents of tuberculosis and malaria, synthesize the essential isoprenoid precursor isopentenyl diphosphate via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway rather than the classical mevalonate pathway that is found in humans. As part of a structure-based drug-discovery program against tuberculosis, DXR, the enzyme that carries out the second step in the MEP pathway, has been investigated. This enzyme is the target for the antibiotic fosmidomycin and its active acetyl derivative FR-900098. The structure of DXR from Mycobacterium tuberculosis in complex with FR-900098, manganese and the NADPH cofactor has been solved and refined. This is a new crystal form that diffracts to a higher resolution than any other DXR complex reported to date. Comparisons with other ternary complexes show that the conformation is that of the enzyme in an active state: the active-site flap is well defined and the cofactor-binding domain has a conformation that brings the NADPH into the active site in a manner suitable for catalysis. The substrate-binding site is highly conserved in a number of pathogens that use this pathway, so any new inhibitor that is designed for the M. tuberculosis enzyme is likely to exhibit broad-spectrum activity. Structural studies on Mycobacterium tuberculosis DXR in complex with the antibiotic FR-900098.,Bjorkelid C, Bergfors T, Unge T, Mowbray SL, Jones TA Acta Crystallogr D Biol Crystallogr. 2012 Feb;68(Pt 2):134-43. Epub 2012 Jan 6. PMID:22281742 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DXP reductoisomerase 3D Structures

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