CRYSTAL-STRUCTURE OF THE ESCHERICHIA-COLI DUTPASE IN COMPLEX WITH A SUBSTRATE-ANALOG (DUDP)

We have determined the structure of the homotrimeric dUTPase from Esch erichia coli, complexed with an inhibitor and substrate analogue, dUDP . Three molecules of dUDP are found symmetrically bound per trimer, ea ch in a shallow cleft between adjacent subunits, interacting with evol utionary conserved residues. The interactions of the uracil ring and t he deoxypentose with the protein are consistent with the high specific ity of the enzyme with respect to these groups. The positions of the t wo phosphate groups and adjacent water molecules are discussed in rela tion to the mechanism and kinetics of catalysis. The role that dUTPase plays in DNA metabolism makes the enzyme a potential target for chemo therapeutic drugs: the results presented here will aid in the design a nd development of inhibitory compounds.