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

Chembiochem. 2017 Nov 2;18(21):2137-2144. doi: 10.1002/cbic.201700363. Epub 2017 Oct 2.

Abstract

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.

Keywords: In silico docking; LytB/IspH; MEP pathway inhibitors; X-ray crystallography; [4Fe-4S] cluster.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Erythritol / analogs & derivatives*
  • Erythritol / metabolism
  • Escherichia coli / drug effects*
  • Escherichia coli / enzymology*
  • Escherichia coli Proteins / antagonists & inhibitors
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / metabolism
  • Molecular Docking Simulation
  • Molecular Structure
  • Oxidoreductases / antagonists & inhibitors
  • Oxidoreductases / chemistry*
  • Oxidoreductases / metabolism
  • Sugar Phosphates / metabolism*

Substances

  • 2-C-methylerythritol 4-phosphate
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Sugar Phosphates
  • Oxidoreductases
  • ispH protein, E coli
  • Erythritol