3OB7

Human Thymidylate Synthase R163K with Cys 195 covalently modified by Glutathione

Summary for 3OB7

• Entry DOI: 10.2210/pdb3ob7/pdb
• Related: 3H9K 3HB8
• Descriptor: Thymidylate synthase, GLUTATHIONE, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: methyltransferase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P04818
• Total number of polymer chains: 5
• Total formula weight: 179574.19

Authors

Gibson, L.M.,Celeste, L.R.,Lovelace, L.L.,Lebioda, L. (deposition date: 2010-08-06, release date: 2010-12-22, Last modification date: 2023-09-06)

Primary citation

Gibson, L.M.,Celeste, L.R.,Lovelace, L.L.,Lebioda, L.
Structures of human thymidylate synthase R163K with dUMP, FdUMP and glutathione show asymmetric ligand binding.
Acta Crystallogr.,Sect.D, 67:60-66, 2011

PubMed Abstract: 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 hTS binds this ligand. Interestingly, the two types of binding observed are both asymmetric. In one subunit of the physiological dimer covalent modification of the catalytic nucleophile Cys195 takes place, while in another dimer a noncovalent adduct with reduced glutathione is formed in one of the active sites.

PubMed: 21206062
DOI: 10.1107/S0907444910044732

Experimental method

X-RAY DIFFRACTION (2.75 Å)