1jtq: Difference between revisions
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[[Image:1jtq.gif|left|200px]] | [[Image:1jtq.gif|left|200px]] | ||
'''E. coli TS Complex with dUMP and the Pyrrolo(2,3-d)pyrimidine-based Antifolate LY341770''' | {{Structure | ||
|PDB= 1jtq |SIZE=350|CAPTION= <scene name='initialview01'>1jtq</scene>, resolution 2.50Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=UMP:2'-DEOXYURIDINE+5'-MONOPHOSPHATE'>UMP</scene> and <scene name='pdbligand=LY3:2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-4-(2H-TETRAZOL-5-YL)-BUTYRIC ACID'>LY3</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= THYA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 Escherichia coli]) | |||
}} | |||
'''E. coli TS Complex with dUMP and the Pyrrolo(2,3-d)pyrimidine-based Antifolate LY341770''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1JTQ is a [ | 1JTQ 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=1JTQ OCA]. | ||
==Reference== | ==Reference== | ||
Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases., Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM, J Mol Biol. 2001 Nov 2;313(4):813-29. PMID:[http:// | Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases., Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM, J Mol Biol. 2001 Nov 2;313(4):813-29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11697906 11697906] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: dtmp synthesis]] | [[Category: dtmp synthesis]] | ||
''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 12:08:19 2008'' | ||
Revision as of 13:08, 20 March 2008
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| , resolution 2.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | THYA (Escherichia coli) | ||||||
| Activity: | Thymidylate synthase, with EC number 2.1.1.45 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
E. coli TS Complex with dUMP and the Pyrrolo(2,3-d)pyrimidine-based Antifolate LY341770
OverviewOverview
Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate compounds, developed as inhibitors of thymidylate synthase (TS) in a strategy to circumvent drug-resistance, have been determined in complexes with their in vivo target, human thymidylate synthase, and with the structurally best-characterized Escherichia coli enzyme, to resolutions of 2.2-3.0 A. The 2.9 A crystal structure of a complex of human TS with one of the inhibitors, the multi-targeted antifolate LY231514, demonstrates that this compound induces a "closed" enzyme conformation and leads to formation of a covalent bond between enzyme and substrate. This structure is one of the first liganded human TS structures, and its solution was aided by mutation to facilitate crystallization. Structures of three other pyrrolo(2,3-d)pyrimidine-based antifolates in complex with Escherichia coli TS confirm the orientation of this class of inhibitors in the active site. Specific interactions between the polyglutamyl moiety and a positively charged groove on the enzyme surface explain the marked increase in affinity of the pyrrolo(2,3-d)pyrimidine inhibitors once they are polyglutamylated, as mediated in vivo by the cellular enzyme folyl polyglutamate synthetase.
About this StructureAbout this Structure
1JTQ is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
ReferenceReference
Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases., Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM, J Mol Biol. 2001 Nov 2;313(4):813-29. PMID:11697906
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