1ju6

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[[Image:1ju6.jpg|left|200px]]<br /><applet load="1ju6" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1ju6.jpg|left|200px]]
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caption="1ju6, resolution 2.89&Aring;" />
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'''Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate'''<br />
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{{Structure
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|PDB= 1ju6 |SIZE=350|CAPTION= <scene name='initialview01'>1ju6</scene>, resolution 2.89&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=UMP:2'-DEOXYURIDINE+5'-MONOPHOSPHATE'>UMP</scene> and <scene name='pdbligand=LYA:2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID'>LYA</scene>
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|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]
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|GENE=
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}}
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'''Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate'''
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==Overview==
==Overview==
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==Disease==
==Disease==
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Known disease associated with this structure: Timothy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114205 114205]]
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Known diseases associated with this structure: Brugada syndrome 3 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114205 114205]], Timothy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=114205 114205]]
==About this Structure==
==About this Structure==
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1JU6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=UMP:'>UMP</scene> and <scene name='pdbligand=LYA:'>LYA</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=1JU6 OCA].
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1JU6 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JU6 OCA].
==Reference==
==Reference==
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=11697906 11697906]
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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: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: dtmp synthesis]]
[[Category: dtmp synthesis]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:26:45 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:08:29 2008''

Revision as of 10:08, 20 March 2008

Image:1ju6.jpg


PDB ID 1ju6

Drag the structure with the mouse to rotate
, resolution 2.89Å
Ligands: , and
Activity: Thymidylate synthase, with EC number 2.1.1.45
Coordinates: save as pdb, mmCIF, xml



Human Thymidylate Synthase Complex with dUMP and LY231514, A Pyrrolo(2,3-d)pyrimidine-based Antifolate


Contents

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.

Disease

Known diseases associated with this structure: Brugada syndrome 3 OMIM:[114205], Timothy syndrome OMIM:[114205]

About this Structure

1JU6 is a Single protein structure of sequence from Homo sapiens. 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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