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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
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 …
Structure Of Human Thymidylate Synthase Under Low-Salt Conditions, Leslie L. Lovelace, Wladek Minor, Lukasz Lebioda
Structure Of Human Thymidylate Synthase Under Low-Salt Conditions, Leslie L. Lovelace, Wladek Minor, Lukasz Lebioda
Faculty Publications
Human thymidylate synthase, a target in cancer chemotherapy, was crystallized from PEG 3350 with 30 mM ammonium sulfate (AS) in the crystallization medium. The crystals are isomorphous with the high-salt crystals (~2.0 M AS) and the structure has been solved and refined (R = 22.6%, Rfree = 24.3%) at 1.8 Å resolution. The high- and low-AS-concentration structures are quite similar, with loop 181-197 is in the inactive conformation. Also, residues 95-106 and 129-135 (eukaryotic inserts region) show high mobility as assessed by poor electron density and high values of crystallographic temperature factors (residues 1-25 and 108-129 are disordered in both …