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Crystal structure of shikimate kinase from Mycobacterium tuberculosis reveals the dynamic role of the LID domain in catalysis

  1. Author:
    Gu, Y. J.
    Reshetnikova, L.
    Li, Y.
    Wu, Y.
    Yan, H. G.
    Singh, S.
    Ji, X. H.

  2. Author Address

    Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA Univ Pittsburgh, Univ Pittsburgh Canc Inst, Sch Med, Pittsburgh, PA 15620 USA Univ Pittsburgh, Dept Pharmacol, Sch Med, Pittsburgh, PA 15620 USA Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA Ji XH Natl Canc Inst, Macromol Crystallog Lab, Frederick, MD 21702 USA
    1. Year: 2002
  2. Journal: Journal of Molecular Biology
    1. 319
    2. 3
    3. Pages: 779-789
  4. Type of Article: Article
  1. Abstract:

    Shikimate kinase (SK) and other enzymes in the shikimate pathway are potential targets for developing non-toxic antimicrobial agents, herbicides, and anti-parasite drugs, because the pathway is essential in the above species but is absent from mammals. The crystal structure of Mycobacterium tuberculosis SK (MtSK) in complex with MgADP has been determined at 1.8 Angstrom resolution, revealing critical information for the structure-based design of novel anti-M. tuberculosis agents. MtSK, with a five-stranded parallel beta- sheet flanked by eight alpha-helices, has three domains: the CORE domain, the shikimate-binding domain (SB), and the LID domain. The ADP molecule is bound with its adenine moiety sandwiched between the side-chains of Arg110 and Pro155, its beta-phosphate group in the P-loop, and the alpha and beta- phosphate groups hydrogen bonded to the guanidinium group of Arg117. Arg117 is located in the LID domain, is strictly conserved in SK sequences, is observed for the first time to interact with any bound nucleotide, and appears to be important in both substrate binding and catalysis. The crystal structure of MtSK (this work) and that of Erwinia chrysanthemi SK suggest a concerted conformational change of the LID and SB domains upon nucleotide binding. (C) 2002 Elsevier Science Ltd. All rights reserved.

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