1tys

WATER-MEDIATED SUBSTRATE(SLASH)PRODUCT DISCRIMINATION: THE PRODUCT COMPLEX OF THYMIDYLATE SYNTHASE AT 1.83 ANGSTROMS

spinqualitylabelsall models 1tys, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1tys is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: CXM, DHF, TMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TYSY_ECOLI Provides the sole de novo source of dTMP for DNA biosynthesis. This protein also binds to its mRNA thus repressing its own translation. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate synthase 3D structures

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