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X-Ray Crystal Structures of the Inhibitors Actinonin and BB-3497 Bound to E. coli Peptide Deformylase.

BAKER P, RODGERS F, BARYNIN V, RICE D, BECKETT P, BROWN A, CLEMENTS JM, HUNTER MG, LOBEL M, PALAN S, WHITTAKER M; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 229.

Univ. of Sheffield, Sheffield, United Kingdom

Peptide deformylase (PDF) is a bacterial metalloenzyme that specifically deformylates newly synthesised peptides as an essential part of their post-translational processing. The formylation-deformylation mechanism is not used by eukaryotes and therefore inhibition of PDF represents an attractive target for antibacterial chemotherapy. By screening a library of metalloenzyme inhibitors against PDF from E. coli we identified the natural antibiotic actinonin (1) and the related N-formyl-hydroxylamine derivative BB-3497 (2) as potent inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we purified the PDF.Ni enzyme from E. coli, co-crystallised it with each inhibitor and determined the structures at a resolution of 1.75 A and 2.10 A, respectively. In both complexes, the metal atom is penta-coordinated by the metal binding amino acid residues of the protein (His132, His 136 and Cys90) and the two oxygen atoms of the hydroxamate (actinonin) or the N-formyl-hydroxylamine (BB-3497). In addition, there is extensive hydrogen bonding between the enzyme and the metal binding groups and between the enzyme and the amide backbone of the inhibitors. The n-butyl and n-pentyl chains, which mimic the methionine side chain of the natural substrate, provide a key recognition element by hydrophobic interaction with the S1 pocket, delineated by the residues Ile44, Ile86, Glu88, Leu125, Ile 129 and His132. In contrast, the P[2] and P[3] sidechains of both bound inhibitors are largely exposed to solvent and therefore offer potential sites for modification. This information has been used to facilitate the design of synthetic PDF inhibitors with improved antibacterial potency and in vivo activity. [table: see text]KEYWORDS: Actinonin; Deformylase; Structure

Publication Types:
  • Meeting Abstracts
  • Amidohydrolases
  • Anti-Bacterial Agents
  • BB3497
  • Crystallization
  • Hydroxamic Acids
  • Metalloproteins
  • Metals
  • X-Rays
  • actinonin
  • antagonists & inhibitors
  • peptide deformylase
  • radiography
Other ID:
  • GWAIDS0010847
UI: 102248345

From Meeting Abstracts

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