1tys
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(New page: 200px<br /><applet load="1tys" size="450" color="white" frame="true" align="right" spinBox="true" caption="1tys, resolution 1.8Å" /> '''WATER-MEDIATED SUBSTR...)
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Revision as of 01:35, 21 November 2007
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WATER-MEDIATED SUBSTRATE(SLASH)PRODUCT DISCRIMINATION: THE PRODUCT COMPLEX OF THYMIDYLATE SYNTHASE AT 1.83 ANGSTROMS
Overview
In an irreversible enzyme-catalyzed reaction, strong binding of the, products would lead to substantial product inhibition. The X-ray crystal, structure of the product complex of thymidylate synthase (1.83-A, resolution, R factor = 0.183 for all data between 7.0 and 1.83 A), identifies a bound water molecule that serves to disfavor binding of the, product nucleotide, dTMP. This water molecule is hydrogen bonded to, absolutely conserved Tyr 146 (using the Lactobacillus casei numbering, system) and is displaced by the C7 methyl group of the reaction product, thymidylate. The relation between this observation and kinetic and, thermodynamic values is discussed. The structure reveals a carbamate, modified N-terminus that binds in a highly conserved site, replaced by, side chains that can exploit the same site in other TS sequences. The, enzyme-products complex is compared to the previously determined structure, of enzyme-substrate-cofactor analog. This comparison reveals changes that, occur between the first covalent complex formed between enzyme and, substrate with an inhibitory cofactor analog and the completed reaction., The almost identical arrangement of ligands in these two structures, contributes to our model for the TS reaction and verifies the, physiological relevance of the mode in which potent inhibitors bind to, this target for rational drug design.
About this Structure
1TYS is a Single protein structure of sequence from Escherichia coli with TMP and DHF as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
Reference
Water-mediated substrate/product discrimination: the product complex of thymidylate synthase at 1.83 A., Fauman EB, Rutenber EE, Maley GF, Maley F, Stroud RM, Biochemistry. 1994 Feb 15;33(6):1502-11. PMID:8312270
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