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Further Insight into Crystal Structures of Escherichia coli IspH/LytB in Complex with Two Potent Inhibitors of the MEP Pathway: A Starting Point for Rational Design of New Antimicrobials
Author(s) -
Borel Franck,
Barbier Elodie,
Krasutsky Sergiy,
Janthawornpong Karnjapan,
Chaig Philippe,
Poulter C. Dale,
Ferrer JeanLuc,
Seemann Myriam
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700363
Subject(s) - escherichia coli , antimicrobial , chemistry , stereochemistry , in silico , rational design , conformational isomerism , biochemistry , computational biology , biology , molecule , genetics , gene , organic chemistry
IspH, also called LytB, a protein involved in the biosynthesis of isoprenoids through the methylerythritol phosphate pathway, is an attractive target for the development of new antimicrobial drugs. Here, we report crystal structures of Escherichia coli IspH in complex with the two most potent inhibitors: ( E )‐4‐mercapto‐3‐methylbut‐2‐en‐1‐yl diphosphate (TMBPP) and ( E )‐4‐amino‐3‐methylbut‐2‐en‐1‐yl diphosphate (AMBPP) at 1.95 and 1.7 Å resolution, respectively. The structure of the E. coli IspH:TMBPP complex exhibited two conformers of the inhibitor. This unexpected feature was exploited to design and evolve new antimicrobial candidates in silico.