4bqs

Crystal structure of Mycobacterium tuberculosis shikimate kinase in complex with ADP and a shikimic acid derivative.

spinqualitylabelsall models 4bqs, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bqs is a 3 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 2.15Å Ligands: ADP, K2Q Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AROK_MYCTU Catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid using ATP as a cosubstrate. Publication Abstract from PubMed Shikimate kinase is an essential enzyme in several pathogenic bacteria and it does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Inspired by the essential enzyme movements, several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 A. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136 and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs. <i>Mycobacterium tuberculosis </i> Shikimate Kinase Inhibitors: Design and Simulation Studies of the Catalytic Turnover<i>,Blanco B, Prado V, Lence E, Otero JM, Garcia-Doval C, van Raaij MJ, Llamas-Saiz AL, Lamb H, Hawkins AR, Gonzalez-Bello C J Am Chem Soc. 2013 Jul 26. PMID:23889343 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Shikimate kinase 3D structures

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