3IQI

Structure of O-Acetylserine Sulfhydrylase in Complex with Peptide MNENI

Summary for 3IQI

• Entry DOI: 10.2210/pdb3iqi/pdb
• Related: 1Y7L 3IQG 3IQH
• Descriptor: Cysteine synthase, MNENI (3 entities in total)
• Functional Keywords: protein-peptide complex, allosteric enzyme, amino-acid biosynthesis, cysteine biosynthesis, pyridoxal phosphate, transferase
• Biological source: Haemophilus influenzae
• Total number of polymer chains: 2
• Total formula weight: 34271.15

Authors

Roderick, S.L. (deposition date: 2009-08-20, release date: 2009-11-17, Last modification date: 2023-11-22)

Primary citation

Salsi, E.,Bayden, A.S.,Spyrakis, F.,Amadasi, A.,Campanini, B.,Bettati, S.,Dodatko, T.,Cozzini, P.,Kellogg, G.E.,Cook, P.F.,Roderick, S.L.,Mozzarelli, A.
Design of o-acetylserine sulfhydrylase inhibitors by mimicking nature.
J.Med.Chem., 53:345-356, 2010

PubMed Abstract: The inhibition of cysteine biosynthesis in prokaryotes and protozoa has been proposed to be relevant for the development of antibiotics. Haemophilus influenzae O-acetylserine sulfhydrylase (OASS), catalyzing l-cysteine formation, is inhibited by the insertion of the C-terminal pentapeptide (MNLNI) of serine acetyltransferase into the active site. Four-hundred MNXXI pentapeptides were generated in silico, docked into OASS active site using GOLD, and scored with HINT. The terminal P5 Ile accounts for about 50% of the binding energy. Glu or Asp at position P4 and, to a lesser extent, at position P3 also significantly contribute to the binding interaction. The predicted affinity of 14 selected pentapeptides correlated well with the experimentally determined dissociation constants. The X-ray structure of three high affinity pentapeptide-OASS complexes were compared with the docked poses. These results, combined with a GRID analysis of the active site, allowed us to define a pharmacophoric scaffold for the design of peptidomimetic inhibitors.

PubMed: 19928859
DOI: 10.1021/jm901325e

Experimental method

X-RAY DIFFRACTION (1.7 Å)