1jtu
From Proteopedia
(New page: 200px<br /><applet load="1jtu" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jtu, resolution 2.20Å" /> '''E. coli Thymidylate ...) |
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| - | [[Image:1jtu.gif|left|200px]]<br /><applet load="1jtu" size=" | + | [[Image:1jtu.gif|left|200px]]<br /><applet load="1jtu" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1jtu, resolution 2.20Å" /> | caption="1jtu, resolution 2.20Å" /> | ||
'''E. coli Thymidylate Synthase in a Complex with dUMP and LY338913, A Polyglutamylated Pyrrolo(2,3-d)pyrimidine-based Antifolate'''<br /> | '''E. coli Thymidylate Synthase in a Complex with dUMP and LY338913, A Polyglutamylated Pyrrolo(2,3-d)pyrimidine-based Antifolate'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Crystal structures of four pyrrolo(2,3-d)pyrimidine-based antifolate | + | 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 Structure== | ==About this Structure== | ||
| - | 1JTU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with UMP and LYB as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1JTU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=UMP:'>UMP</scene> and <scene name='pdbligand=LYB:'>LYB</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JTU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Thymidylate synthase]] | [[Category: Thymidylate synthase]] | ||
[[Category: Biermann, D.]] | [[Category: Biermann, D.]] | ||
| - | [[Category: Finer-Moore, J | + | [[Category: Finer-Moore, J S.]] |
| - | [[Category: Fritz, T | + | [[Category: Fritz, T A.]] |
| - | [[Category: Gates, S | + | [[Category: Gates, S B.]] |
| - | [[Category: MacKellar, W | + | [[Category: MacKellar, W C.]] |
| - | [[Category: Patel, V | + | [[Category: Patel, V F.]] |
| - | [[Category: Sayre, P | + | [[Category: Sayre, P H.]] |
| - | [[Category: Stroud, R | + | [[Category: Stroud, R M.]] |
[[Category: LYB]] | [[Category: LYB]] | ||
[[Category: UMP]] | [[Category: UMP]] | ||
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[[Category: polyglutamylation]] | [[Category: polyglutamylation]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:26:39 2008'' |
Revision as of 11:26, 21 February 2008
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E. coli Thymidylate Synthase in a Complex with dUMP and LY338913, A Polyglutamylated Pyrrolo(2,3-d)pyrimidine-based Antifolate
Overview
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 Structure
1JTU is a Single protein structure of sequence from Escherichia coli with and as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
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:11697906
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