2onb

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Revision as of 11:06, 21 November 2007

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spinqualitylabelsall models 2onb, resolution 2.700Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human Thymidylate Synthase at low salt conditions with PDPA bound

Overview

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 muM, PDPA is an uncompetitive inhibitor, while at PDPA, concentrations higher than 1 muM 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.

About this Structure

2ONB is a Single protein structure of sequence from Homo sapiens with SO4, EDO and 7PA as ligands. Full crystallographic information is available from OCA.

Reference

Cooperative inhibition of human thymidylate synthase by mixtures of active site binding and allosteric inhibitors(,)., Lovelace LL, Gibson LM, Lebioda L, Biochemistry. 2007 Mar 13;46(10):2823-30. Epub 2007 Feb 13. PMID:17297914

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