1tsd

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(New page: 200px<br /><applet load="1tsd" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tsd, resolution 1.95&Aring;" /> '''THYMIDYLATE SYNTHASE...)
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caption="1tsd, resolution 1.95&Aring;" />
'''THYMIDYLATE SYNTHASE COMPLEX WITH 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP) AND FOLATE ANALOG 1843U89'''<br />
'''THYMIDYLATE SYNTHASE COMPLEX WITH 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP) AND FOLATE ANALOG 1843U89'''<br />
==Overview==
==Overview==
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The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at, sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 A, crystal structure of Escherichia coli TS bound to the drug and dUMP, reveals that the 1843U89 binding surface includes a hydrophobic patch that, is normally buried. To reach this patch, 1843U89 inserts into the wall of, the TS active site, resulting in a severe local distortion of the protein., In this new conformation, active-site groups that normally bind to the, catalytic cofactor methylene-tetrahydrofolate instead bind to 1843U89 in, new ways. This structure provides a rare example of a protein that can, bind tightly to distinct substances using a single, flexible, binding, surface. This has implications for drug design, as 1843U89 could not have, been obtained from current structure-based approaches.
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The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 A crystal structure of Escherichia coli TS bound to the drug and dUMP reveals that the 1843U89 binding surface includes a hydrophobic patch that is normally buried. To reach this patch, 1843U89 inserts into the wall of the TS active site, resulting in a severe local distortion of the protein. In this new conformation, active-site groups that normally bind to the catalytic cofactor methylene-tetrahydrofolate instead bind to 1843U89 in new ways. This structure provides a rare example of a protein that can bind tightly to distinct substances using a single, flexible, binding surface. This has implications for drug design, as 1843U89 could not have been obtained from current structure-based approaches.
==About this Structure==
==About this Structure==
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1TSD 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 BME, UMP and F89 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1TSD OCA].
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1TSD 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=BME:'>BME</scene>, <scene name='pdbligand=UMP:'>UMP</scene> and <scene name='pdbligand=F89:'>F89</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=1TSD OCA].
==Reference==
==Reference==
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[[Category: Single protein]]
[[Category: Single protein]]
[[Category: Thymidylate synthase]]
[[Category: Thymidylate synthase]]
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[[Category: Montfort, W.R.]]
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[[Category: Montfort, W R.]]
[[Category: Weichsel, A.]]
[[Category: Weichsel, A.]]
[[Category: BME]]
[[Category: BME]]
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[[Category: dump]]
[[Category: dump]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 03:33:26 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:16:54 2008''

Revision as of 13:16, 21 February 2008

Image:1tsd.gif

1tsd, resolution 1.95Å

Drag the structure with the mouse to rotate

THYMIDYLATE SYNTHASE COMPLEX WITH 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP) AND FOLATE ANALOG 1843U89

Overview

The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 A crystal structure of Escherichia coli TS bound to the drug and dUMP reveals that the 1843U89 binding surface includes a hydrophobic patch that is normally buried. To reach this patch, 1843U89 inserts into the wall of the TS active site, resulting in a severe local distortion of the protein. In this new conformation, active-site groups that normally bind to the catalytic cofactor methylene-tetrahydrofolate instead bind to 1843U89 in new ways. This structure provides a rare example of a protein that can bind tightly to distinct substances using a single, flexible, binding surface. This has implications for drug design, as 1843U89 could not have been obtained from current structure-based approaches.

About this Structure

1TSD 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

Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancer drug 1843U89., Weichsel A, Montfort WR, Nat Struct Biol. 1995 Dec;2(12):1095-101. PMID:8846221

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