3egy

Crystal Structure of Human Thymidyalte Synthase A191K with Loop 181-197 stabilized in the inactive conformation

spinqualitylabelsall models 3egy, resolution 2.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3egy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.18Å Ligands: CME, EDO, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TYSY_HUMAN Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. 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 Loop 181-197 of human thymidylate synthase (hTS) populates two major conformations, essentially corresponding to the loop flipped by 180 degrees . In one of the conformations, the catalytic Cys195 residue lies distant from the active site making the enzyme inactive. Ligands stabilizing this inactive conformation may function as allosteric inhibitors. To facilitate the search for such inhibitors, we have expressed and characterized several mutants designed to shift the equilibrium toward the inactive conformer. In most cases, the catalytic efficiency of the mutants was only somewhat impaired with values of k(cat)/K(m) reduced by factors in a 2-12 range. One of the mutants, M190K, is however unique in having the value of k(cat)/K(m) smaller by a factor of approximately 7500 than the wild type. The crystal structure of this mutant is similar to that of the wt hTS with loop 181-197 in the inactive conformation. However, the direct vicinity of the mutation, residues 188-194 of this loop, assumes a different conformation with the positions of C(alpha) shifted up to 7.2 A. This affects region 116-128, which became ordered in M190K while it is disordered in wt. The conformation of 116-128 is however different than that observed in hTS in the active conformation. The side chain of Lys190 does not form contacts and is in solvent region. The very low activity of M190K as compared to another mutant with a charged residue in this position, M190E, suggests that the protein is trapped in an inactive state that does not equilibrate easily with the active conformer. Variants of human thymidylate synthase with loop 181-197 stabilized in the inactive conformation.,Lovelace LL, Johnson SR, Gibson LM, Bell BJ, Berger SH, Lebioda L Protein Sci. 2009 Aug;18(8):1628-36. PMID:19569192 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate synthase 3D structures

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