E0020

Crystal Structures of the Complexes of Actinonin and Thiorphan with Peptide Deformylase from Staphylococcus aureus. Eric T. Baldwin^#, Melissa S. Harris^#, Joseph B. Moon^#, Anthony W. Yem^§, Cindy L. Wolfe^§, Anne F. Vosters^§, Kimberly A. Curry^%, Joyce I. Cialdella^%, Gloria J. Pokorski^#, Sara E. Morin^%, Gary E. Zurenko^%, Martin R. Deibel, Jr^§, ^#Structural and Computational Chemistry, ^§Protein Sciences, and ^%Infectious Diseases Research, Pharmacia, Research & Development, Kalamazoo, MI 49007.

Initiation of translation in eubacteria begins with formylmethionine-tRNA. As a result, all nascent polypeptides are synthesized with N-formyl methionine at the N-terminus. This formyl group is subsequently removed by Peptide Deformylase (PDF) in order to allow the further post-translational processing of the N-terminus. Removal of the formyl group is essential to cell survival, and it has been shown that deletion of the PDF genes proves lethal. This formylation/deformylation cycle is unique to eubacteria and does not occur in eucaryotic nucleus, thus making the essential deformylation activity of PDF an attractive target for the design of new antibiotics. The X-ray structure of S.aureus peptide deformylase (PDF) enzyme has been determined in complex with the inhibitors: actinonin and thiorphan. These compounds were reported in the literature to be inhibitors of PDF. The X-ray structures were solved using molecular replacement with the un-inhibited structure (1LMH). Both of these complexes were isomorphous with the native crystal form. Both compounds are tethered into the active site using a metal ligand. This ligand is a hydroxymate in actinonin and a thiol is used in thiorphan. Both of these structures are excellent templates for initiation of a program of structure-directed drug design.