F. Scott Mathews

Professor
Department of Biochemistry and Molecular Biophysics
Department of Cell Biology and Physiology

image
flavocytochrome
b2		 image
 
 		 image
monomeric sarcosine
oxidase		 image
para cresol
methylhydroxylase

RESEARCH
The laboratory is engaged in protein structure analysis by X-ray crystallography. The overall aim of this research is to learn how the structure of a protein determines its chemical and physiological properties. One area of interest is the active site structure and mechanism of action of enzymes. A second is the way in which proteins interact with one another. A third area of interest is the structural and evolutionary relationship between and within families of proteins.

Most of the proteins being studied are involved in oxidation-reduction reactions and contain redox active cofactors. These generally fall into two classes, quinoproteins and flavoproteins. Three quinoprotein systems are being studied, a copper amine oxidase containing topaquinone, an alcohol dehydrogenase containing pyrroloquinolinequinone and an amine dehydrogenase containing tryptophan tryptophylquinone. The flavoprotein systems are a flavocytochrome c, an iron-sulfur flavoprotein and a family of FAD-containing secondary amine oxidases. Crystallographic studies are underway to investigate substrate and inhibitor binding as well as mutant forms of these enzymes. In some cases we are also studying interactions of the redox enzymes with small electron carrier proteins.

The physical and chemical techniques used in this laboratory include protein purification and crystallization, x-ray diffraction, computer graphics and molecular biology. A rapid X-ray data acquisition system and several molecular graphics work stations are available.

KEYWORDS

computer graphics, x-ray crystallography, cytochrome, flavoprotein, protein structure

PUBLICATIONS

  • Hassan-Abadallah, A., Zhao, G., Chen, Z., Mathews, F.S. and Schuman Jorns, M. Arginine 49 is a bifunctional residue important in catalysis and biosynthesis of monomeric sarcosine oxidase: A context-sensitive model for the electrostatic impact of arginine to lysine mutations. Biochemistry 47:2913-2922 (2008).
  • Gandhi, P.S., Chen, Z., Mathews, F.S. and Di Cera, E. Structural identification of the pathway of long-range communication in an allosteric enzyme. Proc Natl Acad Sci U S A. 105:1832-1837 (2008).
  • Ma, J.K., Wang, Y., Carrell, C.J., Mathews, F.S. and Davidson, V.L. A single methionine residue dictates the kinetic mechanism of interprotein electron transfer from methylamine dehydrogenase to amicyanin(,). Biochemistry 46:11137-11146 (2007).
  • Carrell, C.J., Bruckner, R.C., Venci, D., Zhao, G., Jorns, M.S. and Mathews, F.S. NikD, an unusual amino acid oxidase essential for nikkomycin biosynthesis: Structures of closed and open forms at 1.15 and 1.90 A resolution. Structure 15:928-941 (2007).
  • Bush-Pelc, L.A., Marino, F., Chen, Z., Pineda, A.O. Mathews, F.S. and Di Cera, E. Important role of the Cys-191: Cys-220 disulfide bond in thrombin function and allostery. J Biol Chem 282:27165-27170 (2007).
  • Bah, A., Chen, Z., Bush-Pelc, L.A., Mathews, F.S. and Di Cera, E. Crystal structures of murine thrombin in complex with the extracellular fragments of murine protease-activated receptors PAR3 and PAR4. Proc Natl Acad Sci U S A. 104:11603-11608 (2007)
  • Ma, J.K., Mathews, F.S. and Davidson, V.L. Correlation of rhombic distortion of the type 1 copper site of M98Q amicyanin with increased electron transfer reorganization energy. Biochemistry 46:8561-8568 (2007).
  • Marino, F., Chen, Z., Ergenekan, C.E., Bush-Pelc, L.A., Mathews, F.S. and Di Cera, E. Structural basis of Na+ activation mimicry in murine thrombin. J Biol Chem. 282L:16355-16361 (2007) .
  • Pineda, A.O., Chen, Z.W., Marino, F., Mathews, F.S., Mosesson, M.W. and Di Cera, E., Crystal structure of thrombin in complex with fibrinogen gamma' peptide. Biophys Chem 125:556-559 (2007).
  • Sukumar, N., Chen, Z.W., Ferrari, D., Merli, A., Rossi, G.L., Bellamy, H.D., Chistoservdov, A., Davidson, V.L. and Mathews, F.S. Crystal structure of an electron transfer complex between aromatic amine dehydrogenase and azurin from Alcaligenes faecalis. Biochemistry 45:13500-13510 (2006).
  • Pineda, A.O., Chen, Z.W., Bah, A., Garvey, L.C., Mathews, F.S. and Di Cera, E. Crystal structure of thrombin in a self-inhibited conformation. J Biol Chem 281:32922-32928 (2006).
  • Hynson, R.M., Mathews, F.S. and Schuman Jorns, M. Identification of a stable flavin-thiolate adduct in heterotetrameric sarcosine oxidase. J Mol Biol 362:656-663 (2006).
  • Ma, J.K. Carrell, C.J., Mathews, F.S. and Dvidson, V.L. Site-directed mutagenesis of proline 52 to glycine in amicyanin converts a true electron reaction into one that is conformationally gated. Biochem 45:8284-8293 (2006).
  • Chen, Z.W., Hassan-Abdulah, A., Zhao, G., Jorns, M.S. and Mathews, F.S. Heterotetrameric sarcosine oxidase: Structure of a diflavin metalloenzyme at 1.85 angstroms resolution. J Mol Biol 360:1000-1018 (2006).
  • Carrell, C.J., Bush, L.A., Mathews, F.S. and Di Cera, E. High resolution crystal structures of free thrombin in the presence of K(+) reveal the molecular basis of monovalent cation selectivity and an inactive slow form. Biophys Chem 121:177-184 (2006).
  • Chen, Z.W., Zhao, G., Martinovic, S., Jorns, M.S. and Mathews, F.S. Structure of the sodium borohydride-reduced N-(cyclopropyl)glycine adduct of the flavoenzyme monomeric sarcosine oxidase. Biochemistry 44:15111-15450 (2005).
  • Papaconstantinou, M.E., Carrell, D.J., Pineda, A.O., Bobofchak, K.M., Mathews, F.S., Flordellis, C.S., Maragoudakis, M.E., Tsopanoglou, N.E. and Di Cera, E. Thrombin functions through its RGD sequence in a non-canonical conformation. J Biol Chem 280:29393-29396 (2005).
  • Toyama, H., Chen, Z.W., Fukumoto, M., Adachi, O., Matsushita, K. and Mathews, F.S. Molecular cloning and structural analysis of quinohemoprotein alcohol dehydrogenase ADH-IIG from Pseudomonas putida HK5. J Mol Biol 352:91-104 (2005).
  • Hassan-Abdallah, A., Zhao, G., Eschenbrenner, M., Chen, Z.W., Mathews, F.S. and Jorns, M.S. Cloning, expression and crystallization of heterotetrameric sarcosine oxidase from Pseudomonas maltophilia. Protein Expression and Purification 43:33-43 (2005).
  • Bobofchak, K.M., Pineda, A.O., Mathews, F.S. and Di Cera, E. Energetic and structural consequences of perturbing Gly-193 in the oxyanion hole of serine proteases. J Biol Chem 280:25644-25650 (2005).
  • Cunane, L.M., Barton, J.D., Chen, Z.W., Le, K.H., Amar, D., Lederer, F. and Mathews, F.S. Crystal structure analysis of recombinant rat kidney long chain hydroxy acid oxidase. Biochemistry 44:1521-1531 (2005).
  • Sun, D., Li, X., Mathews, F.S. and Davidson, V.L. Site-directed mutagenesis of proline 94 to alanine in amicyanin converts a true electron transfer reaction into one that is kinetically coupled. Biochem 44:7200-7206 (2005).
  • de Garavilla, L., Greco, M.N., Sukumar, N., Chen, Z.W., Pineda, A.O., Mathews, F.S., Di Cera, E., Giardino, E.C., Wells, G.I., Haertlein, B.J., Kauffman, J.A., Corcoran, T.W., Derian, C.K., Eckardt, A.J. and Damiano, B.P. A novel, potent dual inhibitor of the leukocyte protease catepsin G and chymase: Molecular mechanism and anti-inflammatory activity in vivo. J Biol Chem. 280:18001-18007 (2005).
  • Sukumar, N., Langen, P., Mathews, F.S., Jones, L.H., Thiyagarajan, P., Schoenborn, B.P. and Davidson, V.L. A preliminary time-of-flight neutron diffraction study on amicyanin from Paracoccus denitrificans. Acta Crystallographica Section D-Biological Crystallography 61:640-642 (2005).
  • Cunane, L.M., Chen, Z.W., McIntire, W.S. and Mathews, F.S. p-Cresol methylhydroxylase: Alteration of the structure of the flavoprotein subunit upon its binding to the cytochrome subunit. Biochem 44:2963-2973 (2005)
  • Pineda, A.O., Chen, Z.W., Caccia, S., Cantwell, A.M., Savvides, S.N., Waksman, G., Mathews, F.S. and Di Cera, E. The anticoagulant thrombin mutant W215A/E217A has a collapsed primary specificity pocket. J Biol Chem 279:39824-39828 (2004).
  • Carrell, C.J., Wang, X., Jones, L., Jarrett, W.L., Davidson, V.L. and Mathews, F.S. Crystallographic and NMR investigation of cobalt-substituted amicyanin. Biochemistry 43:9381-9389 (2004).
  • Carrell, C.J., Sun, D., Jiang, S., Davidson, V.L. and Mathews, F.S. Sturctural studies of two mutants of amicyanin from Paracoccus denitrificans that stabilize the the reduced state of the copper. Biochemistry 43:9372-9380. (2004).
  • Pineda, A.O., Carrell, C.J., Bush, L.A., Prasad, S., Caccia, S., Chen, Z.W., Mathews, F.S. and Di Cera, E. Molecular dissection of na+ binding to thrombin. J Biol Chem 279:31842-31853 (2004).
  • Toyama, H., Mathews, F.S., Adachi, O. and Matsushita, K. Quinohemoprotein alcohol dehydrogenases: Structure, function, and physiology. Archives of Biochemistry and Biophysics 428:10-21 (2004).
  • Ferrari, D., Di Valentin, M., Carbonera, D., Merli, A., Chen, Z. W., Mathews, F. S., Davidson, V. L. and Rossi, G. L. Electron transfer in crystals of the binary and ternary complexes of methylamine dehydrogenase with amicyanin and cytochrome c551i as detected by EPR spectroscopy. J Biol Inorganic Chem 9:231-237 (2004).
  • Sukumar, N. Dewanti, A. R., Mitra, B. and Mathews, F. S. High resolution structures of an oxidized and reduced flavoprotein. The water switch in a soluble form of (S)-mandelate dehydrogenase. J Biol Chem 279:3749-3757 (2004).
  • Sun, D., Ono, K., Okajima, T., Tanizawa, K., Uchida, M. Yamamoto, Y., Mathews, F.S. and Davidson, V.L. Chemical and kinetic reaction mechanisms of quinohemoprotein amine dehydrogenase from Paracocus denitrificans. Biochemistry 42:10896-10903 (2003).
  • Datta, S., Ikeda, T., Kano, K. and Mathews, F.S. Structure of the phenylhydrazine adduct of the quinohemoprotein amine dehydrogenase from Paracoccus denitrificans at 1.7 A resolution. Acta Crystallographic Section D-Biological Crystallography 59:1551-1556 (2003).
  • Sun, D., Chen, Z.W., Mathews, F.S. and Davidson, V.L. Mutation of alphaPhe55 of methylamine dehydrogenase alters the reorganization energy and electronic coupling for its electron transfer reaction with amicyanin. Biochemistry 41:13926-13933 (2002).
  • Zhao, G., Song, H., Chen, Z.W., Mathews, F.S. and Jorns, M.S. Monomeric sarcosine oxidase: Role of histidine 269 in catalysis. Biochemistry 41:9751-9764 (2002).
  • Cunane, L.M., Barton, J.D., Chen, Z.W., Welsh, F.E., Chapman, S.K., Reid, G.A. and Mathews, F.S. Crystallographic study of the recombinant flavin-binding domain of Baker's yeast flavocytochrome b2: Comparison with the tntact wild-type enzyme. Biochemistry 41:4264-4272 (2002).
  • Chen, Z.W., Matsushita, K., Yamashita, T., Fujii, T., Toyama, H., Adachi, O., Bellamy, H.D., and Mathews, F.S. Structure at 1.9 Å resolution of a quinohemoprotein alcohol dehydrogenase from Pseudomonas putida HK5. Structure 10:837-849 (2002).
  • Sukumar, N., Xu, Y., Gatti, D.L., Mitra, B. and Mathews, F.S. Structure of an active soluble mutant of the membrane-associated (S)-mandelate dehydrogenase. Biochemistry 40:9870-9878 (2001).
  • Zheng, Y.J., Xia, Z.X., Chen, Z.W., Mathews, F.S. and Bruice, T.C. Catalytic mechanism of quinoprotein methanol dehydrogenase: A theoretical and x-ray crystallographic investigation. Proceedings of the National Academy of Sciences of the United States of America 98:432-434 (2001).
  • Trickey, P., Basran, J., Lian, L. Y., Chen, Z. W., Barton, J. D., Sutcliffe, M. J., Scutton, N. S., and Mathews, F.S. Structural and biochemical characterization of recombinant wild type and C30A mutant of trimethylamine dehydrogenase from methylophilus methylotrophus. Biochemistry 39:7678-7688 (2000).
  • Mowat, C. G., Beaudoin, J., Durley, R. C., Barton, J. D., Pike, A. D., Chen, Z. W., Reid, G. A., Chapman, S. K., and Mathews, F. S. Kinetic and crystallographic studies on the active site Arg289Lys mutant of flavocytochrome b2. Biochemistry 39:3266-3275 (2000).
  • Cunane, L. M., Chen, Z. W., Shamala, N., Mathews, F. S., Cronin, C.N., and McIntire, W. S. Structures of the flavocytochrome p-cresol methylhydroxylase and its enzyme-substrate complex: Gated substrate entry and proton relays support the proposed catalytic mechanism. J. Mol. Biol. 295:357-374 (2000).
  • Wagner, M. A., Trickey, P., Chen, Z. W., Mathews, F. S., and Jorns, M. S. Monomeric sarcosine oxidase: Flavin reactivity and active site binding determinants. Biochemistry 39:8813-8824 (2000).
  • Chen, Z. W., Schwartz, B., Williams, N. K., Li, R., Klinman, J. P., and Mathews, F. S. Crystal structure at 2.5 Å resolution of zinc-substituted copper amine oxidase of Hansenula Polymorpha expressed in Escherichia coli. Biochemistry 39:9709-9717 (2000).
  • Trickey P, Wagner MA, Jorns MS, et al. Monomeric sarcosine oxidase: structure of a covalently-flavinylated amine oxidizing enzyme. Structure 7:331-345 (1999).
  • Chen L, Doi N, Durley RCE, et al. Refined crystal structure of methylamine dehydrogenase from paracoccus denitrificans at 1.75 Å resolution. J Mol Biol 276:131-149 (1998).
  • Li R, Klinman JP, Mathews FS. Crystal structure of copper amine oxidase from hansenula polymorpha determined at 2.4 resolution. Structure 6:293-307 (1998).
  • Xia Z-X, Dai W-W, Zhang Y-F, et al. Determination of the gene sequence and the three-dimensional structure at 2.4 Å resolution of methanol dehydrogenase from Methylophilus W3A1. J Mol Biol 259:480-501 (1996).

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ADDRESS

Washington University School of Medicine
Department of Biochemistry and Molecular Biophysics
660 S. Euclid Ave., Box 8231
St. Louis, MO 63110

Office: 314-362-1080
Fax: 314-362-7183
Lab: 314-362-1079
2210 Cancer Research Bldg.
F. Scott Mathews