Functional Analysis of Substrate and Cofactor Complex Structures of a Thymidylate Synthase-Complementing Protein

作者: Irimpan I Mathews , Ashley M Deacon , Jaume M Canaves , Daniel McMullan , Scott A Lesley

DOI: 10.1016/S0969-2126(03)00097-2

关键词: Cell survivalEnzymeThermotoga maritimaFAD bindingCofactorTransferaseBiochemistryThymidylate synthaseBiology

摘要: Like thymidylate synthase (TS) in eukaryotes, the synthase-complementing proteins (TSCPs) are mandatory for cell survival of many prokaryotes absence external sources thymidylate. Details mechanism this novel family enzymes unknown. Here, we report structural and functional analysis a TSCP from Thermotoga maritima its complexes with substrate, analogs, cofactor. The structures presented here provide basis rationalizing catalysis reveal possibility design an inhibitor. We have identified new helix-loop-strand FAD binding motif characteristic family. presence hydrophobic core residues conserved among suggests common overall fold.

参考文章(35)
W. Kauzmann, Some factors in the interpretation of protein denaturation. Advances in Protein Chemistry. ,vol. 14, pp. 1- 63 ,(1959) , 10.1016/S0065-3233(08)60608-7
Zbyszek Otwinowski, Wladek Minor, Processing of X-ray diffraction data collected in oscillation mode Methods in Enzymology. ,vol. 276, pp. 307- 326 ,(1997) , 10.1016/S0076-6879(97)76066-X
Robert M. Stroud, Janet S. Finer‐Moore, Stereochemistry of a multistep/bipartite methyl transfer reaction: thymidylate synthase. The FASEB Journal. ,vol. 7, pp. 671- 677 ,(1993) , 10.1096/FASEBJ.7.8.8500692
Rogerio R. Sotelo-Mundo, Joanna Ciesla, Jolanta M. Dzik, Wojciech Rode, Frank Maley, Gladys F. Maley, Larry W. Hardy, William R. Montfort, Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug. Biochemistry. ,vol. 38, pp. 1087- 1094 ,(1999) , 10.1021/BI981881D
Christine E. Foster, Mario A. Bianchet, Paul Talalay, Qinjian Zhao, L. Mario Amzel, Crystal structure of human quinone reductase type 2, a metalloflavoprotein. Biochemistry. ,vol. 38, pp. 9881- 9886 ,(1999) , 10.1021/BI990799V
Wladek Minor, Sondra Berger, H. Trent Spencer, R. Bruce Dunlap, Lukasz Lebioda, Jason Phan, Elahe Mahdavian, Michael C. Nivens, Catalytic cysteine of thymidylate synthase is activated upon substrate binding. Biochemistry. ,vol. 39, pp. 6969- 6978 ,(2000) , 10.1021/BI000367G
R. A. Laskowski, M. W. MacArthur, D. S. Moss, J. M. Thornton, PROCHECK: a program to check the stereochemical quality of protein structures Journal of Applied Crystallography. ,vol. 26, pp. 283- 291 ,(1993) , 10.1107/S0021889892009944
Axel T Brünger, Paul D Adams, G Marius Clore, Warren L DeLano, Piet Gros, Ralf W Grosse-Kunstleve, J-S Jiang, John Kuszewski, Michael Nilges, Navraj S Pannu, Randy J Read, Luke M Rice, Thomas Simonson, Gregory L Warren, Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination Acta Crystallographica Section D-biological Crystallography. ,vol. 54, pp. 905- 921 ,(1998) , 10.1107/S0907444998003254
Orly Dym, David Eisenberg, Sequence-structure analysis of FAD-containing proteins. Protein Science. ,vol. 10, pp. 1712- 1728 ,(2001) , 10.1110/PS.12801