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| - | [[Image:1hw4.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1hw4| PDB=1hw4 | SCENE= }} | | {{STRUCTURE_1hw4| PDB=1hw4 | SCENE= }} |
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| - | '''STRUCTURE OF THYMIDYLATE SYNTHASE SUGGESTS ADVANTAGES OF CHEMOTHERAPY WITH NONCOMPETITIVE INHIBITORS'''
| + | ===STRUCTURE OF THYMIDYLATE SYNTHASE SUGGESTS ADVANTAGES OF CHEMOTHERAPY WITH NONCOMPETITIVE INHIBITORS=== |
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| - | ==Overview==
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| - | Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer and some other neoplasms. The emergence of resistance to the treatment is often related to the increased levels of TS in cancer cells, which have been linked to the elimination of TS binding to its own mRNA upon drug binding, a feedback regulatory mechanism, and/or to the increased stability to intracellular degradation of TS.drug complexes (versus unliganded TS). The active site loop of human TS (hTS) has a unique conformation resulted from a rotation by 180 degrees relative to its orientation in bacterial TSs. In this conformation, the enzyme must be inactive, because the catalytic cysteine is no longer positioned in the ligand-binding pocket. The ordered solvent structure obtained from high resolution crystallographic data (2.0 A) suggests that the inactive loop conformation promotes mRNA binding and intracellular degradation of the enzyme. This hypothesis is supported by fluorescence studies, which indicate that in solution both active and inactive forms of hTS are present. The binding of phosphate ion shifts the equilibrium toward the inactive conformation; subsequent dUMP binding reverses the equilibrium toward the active form. Thus, TS inhibition via stabilization of the inactive conformation should lead to less resistance than is observed with presently used drugs, which are analogs of its substrates, dUMP and CH(2)H(4)folate, and bind in the active site, promoting the active conformation. The presence of an extension at the N terminus of native hTS has no significant effect on kinetic properties or crystal structure.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_11278511}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 11278511 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_11278511}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Methyltransferase]] | | [[Category: Methyltransferase]] |
| | [[Category: Thymidylate synthase]] | | [[Category: Thymidylate synthase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 19:17:26 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 16:25:58 2008'' |
Revision as of 13:26, 28 July 2008
Template:STRUCTURE 1hw4
STRUCTURE OF THYMIDYLATE SYNTHASE SUGGESTS ADVANTAGES OF CHEMOTHERAPY WITH NONCOMPETITIVE INHIBITORS
Template:ABSTRACT PUBMED 11278511
About this Structure
1HW4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors., Phan J, Steadman DJ, Koli S, Ding WC, Minor W, Dunlap RB, Berger SH, Lebioda L, J Biol Chem. 2001 Apr 27;276(17):14170-7. Epub 2001 Jan 24. PMID:11278511
Page seeded by OCA on Mon Jul 28 16:25:58 2008
