Structural studies of Enterococcus faecalismethionine aminopeptidase and design of microbe specific 2,2′-bipyridine based inhibitors

Abstract

Methionine aminopeptidase (MetAP) represents a unique class of proteases that is responsible for removing the N-terminal initiator methionine from newly synthesized proteins. The lone MetAP gene in prokaryotes is essential for the survival of the microorganism suggesting that it could be used as a drug target. Here, we describe the crystal structure of the Enterococcus faecalis MetAP in the apo-form, biochemical characterization, metal affinity and small molecule library screening. Enzyme inhibition and modeling studies of the best inhibitor, 2,2′-bipyridine, were performed. Employing the molecular modeling tools, 2,2′-bipyridine derivatives were generated that could specifically inhibit class specific MetAPs.