標題: Structures of Helicobacter pylori Shikimate Kinase Reveal a Selective Inhibitor-Induced-Fit Mechanism
作者: Cheng, Wen-Chi
Chen, Yen-Fu
Wang, Hung-Jung
Hsu, Kai-Cheng
Lin, Shuang-Chih
Chen, Tzu-Jung
Yang, Jinn-Moon
Wang, Wen-Ching
生物科技學系
生物資訊及系統生物研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
公開日期: 16-三月-2012
摘要: 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 center dot SO4, R57A, and HpSK center dot shikimate-3-phosphate center dot 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.
URI: http://dx.doi.org/e33481
http://hdl.handle.net/11536/16112
ISSN: 1932-6203
DOI: e33481
期刊: PLOS ONE
Volume: 7
Issue: 3
結束頁: 
顯示於類別:期刊論文


文件中的檔案:

  1. 000303309100051.pdf