2ONB
Human Thymidylate Synthase at low salt conditions with PDPA bound
Summary for 2ONB
| Entry DOI | 10.2210/pdb2onb/pdb |
| Related | 1YPV |
| Descriptor | Thymidylate synthetase, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | diphosphonic acid, fdump, zd9331, heteroinhibition, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 36429.59 |
| Authors | Lovelace, L.L.,Gibson, L.M.,Lebioda, L. (deposition date: 2007-01-23, release date: 2007-04-10, Last modification date: 2024-10-30) |
| Primary citation | Lovelace, L.L.,Gibson, L.M.,Lebioda, L. Cooperative Inhibition of Human Thymidylate Synthase by Mixtures of Active Site Binding and Allosteric Inhibitors Biochemistry, 46:2823-2830, 2007 Cited by PubMed Abstract: Thymidylate synthase (TS) is a target in the chemotherapy of colorectal cancer and some other neoplasms. It catalyzes the transfer of a methyl group from methylenetetrahydrofolate to dUMP to form dTMP. On the basis of structural considerations, we have introduced 1,3-propanediphosphonic acid (PDPA) as an allosteric inhibitor of human TS (hTS); it is proposed that PDPA acts by stabilizing an inactive conformer of loop 181-197. Kinetic studies showed that PDPA is a mixed (noncompetitive) inhibitor versus dUMP. In contrast, versus methylenetrahydrofolate at concentrations lower than 0.25 microM, PDPA is an uncompetitive inhibitor, while at PDPA concentrations higher than 1 microM the inhibiton is noncompetive, as expected. At the concentrations corresponding to uncompetitive inhibition, PDPA shows positive cooperativity with an antifolate inhibitor, ZD9331, which binds to the active conformer. PDPA binding leads to the formation of hTS tetramers, but not higher oligomers. These data are consistent with a model in which hTS exists preferably as an asymmetric dimer with one subunit in the active conformation of loop 181-197 and the other in the inactive conformation. PubMed: 17297914DOI: 10.1021/bi061309j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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