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Associate Professor of Biochemistry and Biophysics
Ph.D. University of Rochester 1982
M.D. University of Rochester 1981

The structure of a biologically active molecule (i.e. a drug) is intimately related to its function. Our laboratory employs the technique of macromolecular crystallography to elucidate molecular structure, and to relate this structure to biological function. Crystallographic methods are used to define the structures of complexes between active ligands and their enzymatic targets. This information is used in conjunction with ancillary modeling and computational techniques to identify, at the molecular level, specific interactions important in stabilizing these complexes.

Current research projects examine a series of chemotherapeutic dinucleotide analogues of the cofactor NAD. These agents act as general inhibitors of the class of enzymes known as dehydrogenases. Different inhibitors show marked variations in specificities and affinities for different enzymes. These variations in ligand binding can be attributed to distinct alterations in both intra- and intermolecular interactions observed in the enzyme-inhibitor complexes.

Structural results at atomic resolution are correlated with biochemical and pharmacological data. The ultimate aim of these studies is to identify conformational features which enhance drug activity. These features can then be preserved in the intelligent design of new analogues.

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Recent Publications

Gruswitz F, Frishman M, Goldstein BM, Wedekind JE (2005) Coupling of MBP fusion protein cleavage with sparse matrix crystallization screens to overcome problematic protein solubility. Biotechniques, 39:476, 478, 480

Nogami K, Wakabayashi H, Ansong C, Fay PJ (2004) Localization of a pH-dependent, A2 subunit-interactive surface within the factor VIIIa A1 subunit. Biochim Biophys Acta, 1701:25-35

Ceccarelli C, Liang ZX, Strickler M, Prehna G, Goldstein BM, Klinman JP, Bahnson BJ (2004) Crystal structure and amide H/D exchange of binary complexes of alcohol dehydrogenase from Bacillus stearothermophilus: insight into thermostability and cofactor binding. Biochemistry, 43:5266-77

Strickler M, Goldstein BM, Maxfield K, Shireman L, Kim G, Matteson DS, Jones JP (2003) Crystallographic studies on the complex behavior of nicotine binding to P450cam (CYP101). Biochemistry, 42:11943-50

Pankiewicz KW, Lesiak-Watanabe KB, Watanabe KA, Patterson SE, Jayaram HN, Yalowitz JA, Miller MD, Seidman M, Majumdar A, Prehna G, Goldstein BM (2002) Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. J Med Chem, 45:703-12

French KJ, Rock DA, Manchester JI, Goldstein BM, Jones JP (2002) Active site mutations of cytochrome p450cam alter the binding, coupling, and oxidation of the foreign substrates (R)- and (s)-2-ethylhexanol. Arch Biochem Biophys, 398:188-97

Pankiewicz KW, Watanabe KA, Lesiak-Watanabe K, Goldstein BM, Jayaram HN (2002) The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside. Curr Med Chem, 9:733-41

Franchetti P, Marchetti S, Cappellacci L, Yalowitz JA, Jayaram HN, Goldstein BM, Grifantini M (2001) A new C-nucleoside analogue of tiazofurin: synthesis and biological evaluation of 2-beta-D-ribofuranosylimidazole-4-carboxamide (imidazofurin). Bioorg Med Chem Lett, 11:67-9

French KJ, Strickler MD, Rock DA, Bennett GA, Wahlstrom JL, Goldstein BM, Jones JP (2001) Benign synthesis of 2-ethylhexanoic acid by cytochrome P450cam: enzymatic, crystallographic, and theoretical studies. Biochemistry, 40:9532-8

Franchetti P, Marchetti S, Cappellacci L, Jayaram HN, Yalowitz JA, Goldstein BM, Barascut JL, Dukhan D, Imbach JL, Grifantini M (2000) Synthesis, conformational analysis, and biological activity of C-thioribonucleosides related to tiazofurin. J Med Chem, 43:1264-70

Goldstein BM, Colby TD (2000) Conformational constraints in NAD analogs: implications for dehydrogenase binding and specificity. Adv Enzyme Regul, 40:405-26

Colby TD, Vanderveen K, Strickler MD, Markham GD, Goldstein BM (1999) Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc Natl Acad Sci U S A, 96:3531-6

Goldstein BM, Colby TD (1999) IMP dehydrogenase : structural aspects of inhibitor binding. Curr Med Chem, 6:519-36

Graduate students in my laboratory work toward a Ph.D. degree in the following program[s]:

Ph.D. in Biochemistry
Ph.D. in Biophysics

Ph.D. candidates in my laboratory may also be affiliated with these programs:

Contact Information

E-Mail: Barry_Goldstein@urmc.rochester.edu

Barry M. Goldstein
Department of Biochemistry and Biophysics
University of Rochester School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester, New York 14642

Office: Medical Center 1-6808
Telephone: (585) 275-5095; Fax: (585) 275-6007