Structural insight into the interaction of O-acetylserine sulfhydrylase with competitive, peptidic inhibitors by saturation transfer difference-NMR

FEBS Lett. 2016 Apr;590(7):943-53. doi: 10.1002/1873-3468.12126. Epub 2016 Mar 22.

Abstract

O-acetylserine sulfhydrylase (OASS), the enzyme catalysing the last step of cysteine biosynthesis in bacteria, is involved in antibiotic resistance and biofilm formation. Since mammals lack OASS, it is a potential target for antimicrobials. However, a limited number of inhibitors has been developed and crystallized in complex with OASS. STD-NMR was applied to study the interaction of the inhibitory pentapeptide MNYDI with the CysK and CysM OASS isozymes from Salmonella Typhimurium. Results are in excellent agreement with docking and SAR studies and confirm the important role played by the C-terminal Ile5 and the arylic moiety at P3 in dictating affinity.

Keywords: Saturation Transfer Difference NMR; cysteine biosynthesis; cysteine synthase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / metabolism
  • Antimicrobial Cationic Peptides / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Cysteine Synthase / antagonists & inhibitors*
  • Cysteine Synthase / chemistry
  • Cysteine Synthase / genetics
  • Cysteine Synthase / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Epitope Mapping
  • Haemophilus influenzae / enzymology
  • Hydrogen Bonding
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Models, Molecular*
  • Molecular Docking Simulation
  • Nuclear Magnetic Resonance, Biomolecular
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Peptide Library
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Salmonella typhimurium / enzymology*
  • Structural Homology, Protein

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Isoenzymes
  • Oligopeptides
  • Peptide Library
  • Recombinant Proteins
  • methionyl-asparagyl-tyrosyl-aspartyl-isoleucine
  • Cysteine Synthase