3pfp

Structure of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase from Mycobacterium tuberculosis in complex with an active site inhibitor

spinqualitylabelsall models 3pfp, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3pfp is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: 035, 036, CL, MN, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AROG_MYCTU Catalyzes an aldol-like condensation reaction between phosphoenolpyruvate (PEP) and D-erythrose 4-phosphate (E4P) to generate 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) and inorganic phosphate. Publication Abstract from PubMed Tuberculosis remains a serious global health threat, with the emergence of multidrug-resistant strains highlighting the urgent need for novel antituberculosis drugs. The enzyme 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first step of the shikimate pathway for the biosynthesis of aromatic compounds. This pathway has been shown to be essential in Mycobacterium tuberculosis, the pathogen responsible for tuberculosis. DAH7PS catalyzes a condensation reaction between P-enolpyruvate and erythrose 4-phosphate to give 3-deoxy-D-arabino-heptulosonate 7-phosphate. The enzyme reaction mechanism is proposed to include a tetrahedral intermediate, which is formed by attack of an active site water on the central carbon of P-enolpyruvate during the course of the reaction. Molecular modeling of this intermediate into the active site reported in this study shows a configurational preference consistent with water attack from the re face of P-enolpyruvate. Based on this model, we designed and synthesized an inhibitor of DAH7PS that mimics this reaction intermediate. Both enantiomers of this intermediate mimic were potent inhibitors of M. tuberculosis DAH7PS, with inhibitory constants in the nanomolar range. The crystal structure of the DAH7PS-inhibitor complex was solved to 2.35 A. Both the position of the inhibitor and the conformational changes of active site residues observed in this structure correspond closely to the predictions from the intermediate modeling. This structure also identifies a water molecule that is located in the appropriate position to attack the re face of P-enolpyruvate during the course of the reaction, allowing the catalytic mechanism for this enzyme to be clearly defined. Potent inhibitors of a shikimate pathway enzyme from Mycobacterium tuberculosis: combining mechanism- and modeling-based design.,Reichau S, Jiao W, Walker SR, Hutton RD, Baker EN, Parker EJ J Biol Chem. 2011 May 6;286(18):16197-207. Epub 2011 Mar 15. PMID:21454647 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also DAHP synthase 3D structures

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