Structural basis for the design of antibiotics targeting peptide deformylase

While protein synthesis in bacteria begins with a formylated methionine, th e formyl group of the nascent polypeptide is removed by peptide deformylase . Since eukaryotic protein synthesis does not involve formylation and defor mylation at the N-terminus, there has been increasing interest in peptide d eformylase as a potential target for antibacterial chemotherapy. Toward thi s end and to aid in the design of effective antibiotics targeting peptide d eformylase, the structures of the protein-inhibitor complexes of both the c obalt and the zinc containing Escherichia coli peptide deformylase bound to the transition-state analogue, (S)-2-O-(H-phosphonoxy)-L-caproyl-L-leucyl- p-nitroanilide (PCLNA), have been determined. The proteins for both deformy lase-inhibitor complexes show basically the same fold as for the native enz yme. The PCLNA inhibitor adopts an extended conformation and fits nicely in to a hydrophobic cavity located near the metal site. On the basis of these structures, guidelines for the design of high-affinity deformylase inhibito rs are suggested. As our results show that the protein residues which inter act with the PCLNA inhibitor are conserved over a wide variety of species, we suggest that antibiotics targeting deformylase could have wide applicabi lity.