1i00

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[[Image:1i00.gif|left|200px]]<br /><applet load="1i00" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1i00.gif|left|200px]]
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caption="1i00, resolution 2.5&Aring;" />
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'''CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX'''<br />
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{{Structure
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|PDB= 1i00 |SIZE=350|CAPTION= <scene name='initialview01'>1i00</scene>, resolution 2.5&Aring;
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|SITE=
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|LIGAND= <scene name='pdbligand=UMP:2'-DEOXYURIDINE+5'-MONOPHOSPHATE'>UMP</scene> and <scene name='pdbligand=D16:TOMUDEX'>D16</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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'''CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX'''
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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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1I00 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=UMP:'>UMP</scene> and <scene name='pdbligand=D16:'>D16</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=1I00 OCA].
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1I00 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=1I00 OCA].
==Reference==
==Reference==
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Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP., Almog R, Waddling CA, Maley F, Maley GF, Van Roey P, Protein Sci. 2001 May;10(5):988-96. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11316879 11316879]
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Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP., Almog R, Waddling CA, Maley F, Maley GF, Van Roey P, Protein Sci. 2001 May;10(5):988-96. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11316879 11316879]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: tomudex]]
[[Category: tomudex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:06:32 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:43:43 2008''

Revision as of 09:43, 20 March 2008

Image:1i00.gif


PDB ID 1i00

Drag the structure with the mouse to rotate
, resolution 2.5Å
Ligands: and
Activity: Thymidylate synthase, with EC number 2.1.1.45
Coordinates: save as pdb, mmCIF, xml



CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX


Contents

Overview

The crystal structures of a deletion mutant of human thymidylate synthase (TS) and its ternary complex with dUMP and Tomudex have been determined at 2.0 A and 2.5 A resolution, respectively. The mutant TS, which lacks 23 residues near the amino terminus, is as active as the wild-type enzyme. The ternary complex is observed in the open conformation, similar to that of the free enzyme and to that of the ternary complex of rat TS with the same ligands. This is in contrast to Escherichia coli TS, where the ternary complex with Tomudex and dUMP is observed in the closed conformation. While the ligands interact with each other in identical fashion regardless of the enzyme conformation, they are displaced by about 1.0 A away from the catalytic cysteine in the open conformation. As a result, the covalent bond between the catalytic cysteine sulfhydryl and the base of dUMP, which is the first step in the reaction mechanism of TS and is observed in all ternary complexes of the E. coli enzyme, is not formed. This displacement results from differences in the interactions between Tomudex and the protein that are caused by differences in the environment of the glutamyl tail of the Tomudex molecule. Despite the absence of the closed conformation, Tomudex inhibits human TS ten-fold more strongly than E. coli TS. These results suggest that formation of a covalent bond between the catalytic cysteine and the substrate dUMP is not required for effective inhibition of human TS by cofactor analogs and could have implications for drug design by eliminating this as a condition for lead compounds.

Disease

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

About this Structure

1I00 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP., Almog R, Waddling CA, Maley F, Maley GF, Van Roey P, Protein Sci. 2001 May;10(5):988-96. PMID:11316879

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