1tlc
From Proteopedia
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| - | [[Image:1tlc.gif|left|200px]] | + | [[Image:1tlc.gif|left|200px]] |
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| - | '''THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89''' | + | {{Structure |
| + | |PDB= 1tlc |SIZE=350|CAPTION= <scene name='initialview01'>1tlc</scene>, resolution 2.1Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=DGP:2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE'>DGP</scene> and <scene name='pdbligand=F89:S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC ACID'>F89</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1TLC is a [ | + | 1TLC is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TLC OCA]. |
==Reference== | ==Reference== | ||
| - | Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89., Weichsel A, Montfort WR, Ciesla J, Maley F, Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3493-7. PMID:[http:// | + | Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89., Weichsel A, Montfort WR, Ciesla J, Maley F, Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3493-7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/7724588 7724588] |
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: methyltransferase]] | [[Category: methyltransferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:19:53 2008'' |
Revision as of 12:19, 20 March 2008
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| , resolution 2.1Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Activity: | Thymidylate synthase, with EC number 2.1.1.45 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89
Overview
A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic agent due to its potent and specific inhibition of thymidylate synthase (TS; EC 2.1.1.45), greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary complex. The quantitative binding of dGMP relative to GMP, FdUMP, and dUMP was determined in the presence and absence of U89 by ultrafiltration analysis, which revealed that although the binding of GMP and dGMP could not be detected in the absence of U89 both were bound in its presence. The Kd for dGMP was about the same as that for dUMP and FdUMP, with binding of the latter two nucleotides being increased by two orders of magnitude by U89. An explanation for the binding of dGMP was provided by x-ray diffraction studies that revealed an extensive stacking interaction between the guanine of dGMP and the benzoquinazoline ring of U89 and hydrogen bonds similar to those involved in dUMP binding. In addition, binding energy was provided through a water molecule that formed hydrogen bonds to both N7 of dGMP and the hydroxyl of Tyr-94. Accommodation of the larger dGMP molecule was accomplished through a distortion of the active site and a shift of the deoxyribose moiety to a new position. These rearrangements also enabled the binding of GMP to occur by creating a pocket for the ribose 2' hydroxyl group, overcoming the normal TS discrimination against nucleotides containing the 2' hydroxyl.
About this Structure
1TLC is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89., Weichsel A, Montfort WR, Ciesla J, Maley F, Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3493-7. PMID:7724588
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