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

Roberto Benoni, Thelma A. Pertinhez, Francesca Spyrakis, Silvia Davalli, Sara Pellegrino, Gianluca Paredi, Angelica Pezzotti, Stefano Bettati, Barbara Campanini, Andrea Mozzarelli

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Cysteine can be synthesized in bacteria by either one of the two isozymes CysK and CysM. STD-NMR allows to study protein-ligand binding specificity in solution. Peptidic inhibitors of the two isozymes with MNX1X2I sequence have been developed. An arylic substituent at position X1 improves affinity for CysK. The N-terminal amino acids dictate the specificity for CysM.

Original languageEnglish
Pages (from-to)943-953
Number of pages11
JournalFEBS Letters
Volume590
Issue number7
DOIs
Publication statusPublished - Apr 1 2016

Fingerprint

Cysteine Synthase
Nuclear magnetic resonance
Isoenzymes
Sexually Transmitted Diseases
Cysteine
Bacteria
Salmonella
Mammals
Biosynthesis
Biofilms
Salmonella typhimurium
Microbial Drug Resistance
Protein Binding
Anti-Bacterial Agents
Ligands
Amino Acids
Enzymes
Proteins

Keywords

  • cysteine biosynthesis
  • cysteine synthase
  • Saturation Transfer Difference NMR

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Structural Biology

Cite this

Benoni, R., Pertinhez, T. A., Spyrakis, F., Davalli, S., Pellegrino, S., Paredi, G., ... Mozzarelli, A. (2016). Structural insight into the interaction of O-acetylserine sulfhydrylase with competitive, peptidic inhibitors by saturation transfer difference-NMR. FEBS Letters, 590(7), 943-953. https://doi.org/10.1002/1873-3468.12126

Structural insight into the interaction of O-acetylserine sulfhydrylase with competitive, peptidic inhibitors by saturation transfer difference-NMR. / Benoni, Roberto; Pertinhez, Thelma A.; Spyrakis, Francesca; Davalli, Silvia; Pellegrino, Sara; Paredi, Gianluca; Pezzotti, Angelica; Bettati, Stefano; Campanini, Barbara; Mozzarelli, Andrea.

In: FEBS Letters, Vol. 590, No. 7, 01.04.2016, p. 943-953.

Research output: Contribution to journalArticle

Benoni, R, Pertinhez, TA, Spyrakis, F, Davalli, S, Pellegrino, S, Paredi, G, Pezzotti, A, Bettati, S, Campanini, B & Mozzarelli, A 2016, 'Structural insight into the interaction of O-acetylserine sulfhydrylase with competitive, peptidic inhibitors by saturation transfer difference-NMR', FEBS Letters, vol. 590, no. 7, pp. 943-953. https://doi.org/10.1002/1873-3468.12126
Benoni, Roberto ; Pertinhez, Thelma A. ; Spyrakis, Francesca ; Davalli, Silvia ; Pellegrino, Sara ; Paredi, Gianluca ; Pezzotti, Angelica ; Bettati, Stefano ; Campanini, Barbara ; Mozzarelli, Andrea. / Structural insight into the interaction of O-acetylserine sulfhydrylase with competitive, peptidic inhibitors by saturation transfer difference-NMR. In: FEBS Letters. 2016 ; Vol. 590, No. 7. pp. 943-953.
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