1juj: Difference between revisions

Revision as of 20:54, 1 July 2008

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File:1juj.png

Template:STRUCTURE 1juj

Human Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based AntifolateHuman Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based Antifolate

Template:ABSTRACT PUBMED 11697906

About this StructureAbout this Structure

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

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-[[Image:1juj.gif|left|200px]]
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 {{STRUCTURE_1juj|  PDB=1juj  |  SCENE=  }}
-'''Human Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based Antifolate'''
+===Human Thymidylate Synthase Bound to dUMP and LY231514, a Pyrrolo(2,3-d)pyrimidine-based Antifolate===
-==Overview==
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-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.
+The line below this paragraph, {{ABSTRACT_PUBMED_11697906}}, adds the Publication Abstract to the page
+(as it appears on PubMed at http://www.pubmed.gov), where 11697906 is the PubMed ID number.
+-->
+{{ABSTRACT_PUBMED_11697906}}
 ==About this Structure==
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 [[Category: Drug resistance]]
 [[Category: Dtmp synthesis]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 21:56:33 2008''
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