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Professor Emeritus James Knox
Education: Ph.D. Boston University; Postdoctoral study, Oxford and Yale Universities
Research Interests: Biophysical and stereochemical analysis of 3D macromolecular structure, especially by means of x-ray scattering and protein crystallography. The tertiary structures and enzymic mechanisms of several bacterial drug targets are being established in an effort to assist medicinal chemists in drug/inhibitor design. Current enzymes under study are the beta- lactamases and transpeptidases which interact with penicillin-type antibiotics, and two D-alanyl ligases of cell wall synthesis which are potential targets of new drugs.
Selected Publications:
Nukaga, M., C. R. Bethel, J. M. Thomson, A. M. Hujer, A. Distler, V. E. Anderson, J. R. Knox and R. A. Bonomo. 2008. Inhibition of class A ß-lactamases by carbapenems: Crystallographic observation of two conformations of meropenem in SHV-1. J. Am. Chem. Soc. 130: 12656–12662.
Sun, T., C. R. Bethe, R. A. Bonomo and J. R. Knox. 2004. Inhibitor-Resistant Class A ß-Lactamases: Consequences of the ser130-to-glycine mutation seen in apo and tazobactam structures of the SHV-1 variant. Biochemistry 43: 14111-14117.
Nukaga, M., T. Abe, A. M. Venkatesan, T. S. Mansour, A. H. Hujer, R. A. Bonomo and J. R. Knox. 2004. Structure-Activity Relationship of 6-Methylidene Penems Bearing Tricyclic Heterocycles as Broad-Spectrum ß-Lactamase Inhibitors: Crystallographic Structures Show Unexpected Binding of 1,4-Thiazepine Intermediates. J. Med. Chem. 47: 6556-6568.
Murthy, N. S. and J. R. Knox. 2004. Hydration of Proteins: SAXS study of native and methoxy-polyethyleneglycol (mPEG)-modified L-asparaginase and bovine serum albumin in mPEG solutions. Biopolymers, 74: 457-466.
Nukaga. M., S. Kumar, K. Nukaga, R. F. Pratt and J. R. Knox. 2004. Hydrolysis of third-generation cephalosporins by class C ß-lactamases: Structures of a transition-state analog of cefotaxime in wild-type and extended-spectrum enzymes. J. Biol. Chem. 279: 9344-9352.
Nukaga, M., T. Abe, A. M. Venkatesan, T. S. Mansour, R. A. Bonomo and J. R. Knox. 2003. Inhibition of class A and class C ß-lactamases by penems: Crystallographic structures of a novel 1,4-thiazepine intermediate. Biochemistry 42: 13152-13159.
Nukaga, M., K. Mayama, A. Hujer, R. A. Bonomo and J. R. Knox. 2003. Ultrahigh resolution structure of a class A beta-lactamase: On the mechanism and specificity of the extended-spectrum SHV-2 enzyme. J. Mol. Biol. 328: 289-301.
Sun, T., M. Nukaga, K. Mayama, E. H. Braswell and J. R. Knox. 2003. Comparison of beta-lactamases of classes A and D: 1.5 Angstrom crystallographic structure of the class D OXA-1 oxacillinase. Protein Sci. 12: 82-91.
McDonough, M. A., J. W. Anderson, N. R. Silvaggi, R. F. Pratt, J. R. Knox and J. A. Kelly. 2002. Structures of two kinetic intermediates reveal species specificity of penicillin binding proteins. J. Mol. Biol. 322: 111-122 (Cover article).
Vakulenko, S. B., D. Golemi, B. Geryk, M. Suvorov, J. R. Knox, S. Mobashery and S. A. Lerner. 2002. Mutational replacement of Leu-293 in the class C Enterobacter cloacae P99 beta-lactamase confers enhanced resistance to cefepime. Antimicrobial Agents & Chemother. 46: 1966-1970.
Nukaga, M., K. Mayama, G. V. Crichlow, T. Sawai and J. R. Knox. 2002. Structure of an extended-spectrum class A beta-lactamase from Proteus vulgaris K1. J. Molec. Biology 317: 109-117.
Sun, T., M. Nukaga, K. Mayama, G. V. Crichlow, A. P. Kuzin and J. R. Knox. 2001. Crystallization and preliminary x-ray study of OXA-1, a class D beta-lactamase. Acta Crystallogr. D57: 1912-1914.
Crichlow, G. V., M. Nukaga, V. Doppalapudi, J. D. Buynak and J. R. Knox. 2001. Inhibition of class C beta-lactamases: Structure of a reaction intermediate with a cephem sulfone. Biochemistry 40: 6233-6239.
Kuzin, A.P, M. Nukaga, Y. Nukaga, A. Hujer, R. A. Bonomo, and J. R. Knox. 2001. Inhibition of the SHV-1 beta-Lactamase by Sulfones: Crystallographic Observation of Two Reaction Intermediates with Tazobactam. Biochemistry 40: 1861-1866. Healy, V. L., I. A. D. Lessard, D. I. Roper, J. R. Knox and C. T. Walsh. 2000. Vancomycin resistance in enterococci: Reprogramming of the D-alanine:D-alanine ligases in bacterial peptidoglycan biosynthesis. Chemistry & Biology 7:R109-R119. Kuzin, A. P., S. Tao, J. Jorczak-Baillass, V. L. Healy, C. T. Walsh and J. R. Knox. 2000.. Enzymes of vancomycin resistance: The structure of D-alanine:D-lactate ligase of naturally-resistant Leuconostoc mesenteroides. Structure 8: 463-470. Crichlow, G. V., A. P. Kuzin, M. Nukaga, K. Mayama, T. Sawai and J. R. Knox. 1999. Structure of the extended-spectrum class C beta-lactamase of Enterobacter cloacae GC1, a natural mutant with a tandem tripeptide insertion. Biochemistry 38:10256-10261. Kuzin, A. P., M. Nukaga, Y. Nukaga, A. Hujer, R. A. Bonomo and J. R. Knox. 1999. Structure of the SHV-1 beta-lactamase. Biochemistry 38:5720-5727. Fan, C., P.C. Moews, I.-L. Park, C.T. Walsh and J.R. Knox. 1997. D-Alanine:D-Alanine Ligase: Phosphonate and Phosphinate Intermediates with Wild-type and the Y216F Mutant. Biochemistry, 36: 2531-2535. Knox, J.R., P.C. Moews and J.-M. Frere. 1996. Molecular Evolution of Bacterial beta-Lactam Resistance. Chemistry & Biology, 3:937-947. Fan, C., P.C. Moews, Y, Shi, C.T. Walsh, and J.R. Knox. 1995. A common fold for peptide synthetases cleaving ATP to ADP: Glutathione synthetase and D-Alanine:D-Alanine ligase. Proc. Natl. Acad. Sci. USA, 92:1172-1176. Knox, J.R. 1995. Extended-spectrum and inhibitor-resistant TEM-type beta-lactamases; mutations, specificity and three-dimensional structure. Antimicrobial Agents and Chemother. (Review) 39:2593-2601.
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