Proteins involved in essential biosynthetic pathways are of particular interest for inhibition studies.¹ One of these proteins is adenosine triphosphate phosphoribosyltransferase (ATP-PRTase), which catalyses the first committed step in the biosynthesis of histidine. ATP-PRTase is unique to prokaryotes and lower eukaryotes making it an interesting target for antimicrobial drug design.² In this work a combination of fragment based lead discovery, protein crystallography and stable substrate analogue synthesis is used to study the mechanism and inhibition of ATP-PRTase and in particular from the organism Mycobacterium tuberculosis (Mtu), the causative agent of tuberculosis.^1,2

The work presented will consider the advantages of FBLD over traditional methods such as high throughput screening. It will illustrate the criteria and design of the fragment library, the use of fragment docking to select for target specific fragments, the techniques used to screen these low affinity binders and will present some of the preliminary results obtained in the search for new effective inhibitors of ATP-PRTase. Crystal structures of ATP-PRTase in complex with both the natural substrate ATP and the natural effectors histidine and AMP will be presented. Their effect on the overall structure will be discussed.