1i00
From Proteopedia
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'''CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX''' | '''CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX''' | ||
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[[Category: Roey, P Van.]] | [[Category: Roey, P Van.]] | ||
[[Category: Waddling, C A.]] | [[Category: Waddling, C A.]] | ||
| - | [[Category: | + | [[Category: Dump]] |
| - | [[Category: | + | [[Category: Human]] |
| - | [[Category: | + | [[Category: Open conformation]] |
| - | [[Category: | + | [[Category: Ternary complex]] |
| - | [[Category: | + | [[Category: Thymidylate synthase]] |
| - | [[Category: | + | [[Category: Tomudex]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 19:24:55 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 16:24, 2 May 2008
CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX
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.
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 Page seeded by OCA on Fri May 2 19:24:55 2008
