Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor-induced-fit mechanism

Wen Chi Cheng, Yen Fu Chen, Hung Jung Wang, Kai Cheng Hsu, Shuang Chih Lin, Tzu Jung Chen, Jinn Moon Yang, Wen Ching Wang

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22 Citations (Scopus)

Abstract

Shikimate kinase (SK), which catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid in the presence of ATP, is the enzyme in the fifth step of the shikimate pathway for biosynthesis of aromatic amino acids. This pathway is present in bacteria, fungi, and plants but absent in mammals and therefore represents an attractive target pathway for the development of new antimicrobial agents, herbicides, and antiparasitic agents. Here we investigated the detailed structure-activity relationship of SK from Helicobacter pylori (HpSK). Site-directed mutagenesis and isothermal titration calorimetry studies revealed critical conserved residues (D33, F48, R57, R116, and R132) that interact with shikimate and are therefore involved in catalysis. Crystal structures of HpSK·SO 4, R57A, and HpSK•shikimate-3-phosphate•ADP show a characteristic three-layer architecture and a conformationally elastic region consisting of F48, R57, R116, and R132, occupied by shikimate. The structure of the inhibitor complex, E114A•162535, was also determined, which revealed a dramatic shift in the elastic LID region and resulted in conformational locking into a distinctive form. These results reveal considerable insight into the active-site chemistry of SKs and a selective inhibitor-induced-fit mechanism.

Original languageEnglish
Article numbere33481
JournalPLoS One
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 16 2012
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Cheng, W. C., Chen, Y. F., Wang, H. J., Hsu, K. C., Lin, S. C., Chen, T. J., Yang, J. M., & Wang, W. C. (2012). Structures of Helicobacter pylori shikimate kinase reveal a selective inhibitor-induced-fit mechanism. PLoS One, 7(3), [e33481]. https://doi.org/10.1371/journal.pone.0033481