4y67 | pdb_00004y67

Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC176, and manganese

spinqualitylabelsall models 4y67, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4y67 is a 2 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: MN, RC5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DXR_PLAF7 Catalyzes the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP). Publication Abstract from PubMed Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth. Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.,Chofor R, Sooriyaarachchi S, Risseeuw MD, Bergfors T, Pouyez J, Johny C, Haymond A, Everaert A, Dowd CS, Maes L, Coenye T, Alex A, Couch RD, Jones TA, Wouters J, Mowbray SL, Van Calenbergh S J Med Chem. 2015 Mar 31. PMID:25781377 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DXP reductoisomerase 3D Structures

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