Engineering Commons^™

Structures Of Human Thymidylate Synthase R163k With Dump, Fdump And Glutathione Show Asymmetric Ligand Binding, Lydia M. Gibson, Lesa R. Celeste, Leslie L. Lovelace, Lukasz Lebioda

Faculty Publications

Thymidylate synthase (TS) is a well validated target in cancer chemotherapy. Here, a new crystal form of the R163K variant of human TS (hTS) with five subunits per asymmetric part of the unit cell, all with loop 181-197 in the active conformation, is reported. This form allows binding studies by soaking crystals in artificial mother liquors containing ligands that bind in the active site. Using this approach, crystal structures of hTS complexes with FdUMP and dUMP were obtained, indicating that this form should facilitate high-throughput analysis of hTS complexes with drug candidates. Crystal soaking experiments using oxidized glutathione revealed that …