Barry Goldstein
| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Biochemistry and Biophysics |
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| Address | University of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 712
Rochester NY 14642
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| Title | Associate Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Medical Humanities |
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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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Gruswitz F, Frishman M, Goldstein BM, Wedekind JE. Coupling of MBP fusion protein cleavage with sparse matrix crystallization screens to overcome problematic protein solubility. Biotechniques. 2005 Oct; 39(4):476, 478, 480.
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Nogami K, Wakabayashi H, Ansong C, Fay PJ. Localization of a pH-dependent, A2 subunit-interactive surface within the factor VIIIa A1 subunit. Biochim Biophys Acta. 2004 Sep 1; 1701(1-2):25-35.
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Ceccarelli C, Liang ZX, Strickler M, Prehna G, Goldstein BM, Klinman JP, Bahnson BJ. Crystal structure and amide H/D exchange of binary complexes of alcohol dehydrogenase from Bacillus stearothermophilus: insight into thermostability and cofactor binding. Biochemistry. 2004 May 11; 43(18):5266-77.
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Strickler M, Goldstein BM, Maxfield K, Shireman L, Kim G, Matteson DS, Jones JP. Crystallographic studies on the complex behavior of nicotine binding to P450cam (CYP101). Biochemistry. 2003 Oct 21; 42(41):11943-50.
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Pankiewicz KW, Watanabe KA, Lesiak-Watanabe K, Goldstein BM, Jayaram HN. The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside. Curr Med Chem. 2002 Apr; 9(7):733-41.
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French KJ, Rock DA, Rock DA, Manchester JI, Goldstein BM, Jones JP. Active site mutations of cytochrome p450cam alter the binding, coupling, and oxidation of the foreign substrates (R)- and (s)-2-ethylhexanol. Arch Biochem Biophys. 2002 Feb 15; 398(2):188-97.
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Pankiewicz KW, Lesiak-Watanabe KB, Watanabe KA, Patterson SE, Jayaram HN, Yalowitz JA, Miller MD, Seidman M, Majumdar A, Prehna G, Goldstein BM. Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. J Med Chem. 2002 Jan 31; 45(3):703-12.
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French KJ, Strickler MD, Rock DA, Rock DA, Bennett GA, Wahlstrom JL, Goldstein BM, Jones JP. Benign synthesis of 2-ethylhexanoic acid by cytochrome P450cam: enzymatic, crystallographic, and theoretical studies. Biochemistry. 2001 Aug 14; 40(32):9532-8.
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Franchetti P, Marchetti S, Cappellacci L, Yalowitz JA, Jayaram HN, Goldstein BM, Grifantini M. A new C-nucleoside analogue of tiazofurin: synthesis and biological evaluation of 2-beta-D-ribofuranosylimidazole-4-carboxamide (imidazofurin). Bioorg Med Chem Lett. 2001 Jan 8; 11(1):67-9.
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Franchetti P, Marchetti S, Cappellacci L, Jayaram HN, Yalowitz JA, Goldstein BM, Barascut JL, Dukhan D, Imbach JL, Grifantini M. Synthesis, conformational analysis, and biological activity of C-thioribonucleosides related to tiazofurin. J Med Chem. 2000 Apr 6; 43(7):1264-70.
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Goldstein BM, Colby TD. Conformational constraints in NAD analogs: implications for dehydrogenase binding and specificity. Adv Enzyme Regul. 2000; 40:405-26.
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Goldstein BM, Colby TD. IMP dehydrogenase : structural aspects of inhibitor binding. Curr Med Chem. 1999 Jul; 6(7):519-36.
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Colby TD, Vanderveen K, Strickler MD, Markham GD, Goldstein BM. Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc Natl Acad Sci U S A. 1999 Mar 30; 96(7):3531-6.
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Colby TD, Bahnson BJ, Chin JK, Klinman JP, Goldstein BM. Active site modifications in a double mutant of liver alcohol dehydrogenase: structural studies of two enzyme-ligand complexes. Biochemistry. 1998 Jun 30; 37(26):9295-304.
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Lesiak K, Watanabe KA, Majumdar A, Powell J, Seidman M, Vanderveen K, Goldstein BM, Pankiewicz KW. Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD. J Med Chem. 1998 Feb 12; 41(4):618-22.
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Bahnson BJ, Colby TD, Chin JK, Goldstein BM, Klinman JP. A link between protein structure and enzyme catalyzed hydrogen tunneling. Proc Natl Acad Sci U S A. 1997 Nov 25; 94(24):12797-802.
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Lesiak K, Watanabe KA, Majumdar A, Seidman M, Vanderveen K, Goldstein BM, Pankiewicz KW. Synthesis of nonhydrolyzable analogues of thiazole-4-carboxamide and benzamide adenine dinucleotide containing fluorine atom at the C2' of adenine nucleoside: induction of K562 differentiation and inosine monophosphate dehydrogenase inhibitory activity. J Med Chem. 1997 Aug 1; 40(16):2533-8.
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Franchetti P, Cappellacci L, Sheikha GA, Jayaram HN, Gurudutt VV, Sint T, Schneider BP, Jones WD, Goldstein BM, Perra G, De Montis A, Loi AG, La Colla P, Grifantini M. Synthesis, structure, and antiproliferative activity of selenophenfurin, an inosine 5'-monophosphate dehydrogenase inhibitor analogue of selenazofurin. J Med Chem. 1997 May 23; 40(11):1731-7.
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Pankiewicz KW, Lesiak K, Zatorski A, Goldstein BM, Carr SF, Sochacki M, Majumdar A, Seidman M, Watanabe KA. The practical synthesis of a methylenebisphosphonate analogue of benzamide adenine dinucleotide: inhibition of human inosine monophosphate dehydrogenase (type I and II). J Med Chem. 1997 Apr 11; 40(8):1287-91.
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Zatorski A, Watanabe KA, Carr SF, Goldstein BM, Pankiewicz KW. Chemical synthesis of benzamide adenine dinucleotide: inhibition of inosine monophosphate dehydrogenase (types I and II). J Med Chem. 1996 Jun 7; 39(12):2422-6.
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Franchetti P, Cappellacci L, Grifantini M, Barzi A, Nocentini G, Yang H, O'Connor A, Jayaram HN, Carrell C, Goldstein BM. Furanfurin and thiophenfurin: two novel tiazofurin analogues. Synthesis, structure, antitumor activity, and interactions with inosine monophosphate dehydrogenase. J Med Chem. 1995 Sep 15; 38(19):3829-37.
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Zatorski A, Goldstein BM, Colby TD, Jones JP, Pankiewicz KW. Potent inhibitors of human inosine monophosphate dehydrogenase type II. Fluorine-substituted analogues of thiazole-4-carboxamide adenine dinucleotide. J Med Chem. 1995 Mar 31; 38(7):1098-105.
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Li H, Hallows WH, Punzi JS, Pankiewicz KW, Watanabe KA, Goldstein BM. Crystallographic studies of isosteric NAD analogues bound to alcohol dehydrogenase: specificity and substrate binding in two ternary complexes. Biochemistry. 1994 Oct 4; 33(39):11734-44.
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Goldstein BM, Li H, Hallows WH, Langs DA, Franchetti P, Cappellacci L, Grifantini M. C-glycosyl bond conformation in oxazofurin: crystallographic and computational studies of the oxazole analogue of tiazofurin. J Med Chem. 1994 May 27; 37(11):1684-8.
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Goldstein BM, Li H, Jones JP, Bell JE, Zeidler J, Pankiewicz KW, Watanabe KA. CNAD: a potent and specific inhibitor of alcohol dehydrogenase. J Med Chem. 1994 Feb 4; 37(3):392-9.
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Li H, Hallows WH, Punzi JS, Marquez VE, Carrell HL, Pankiewicz KW, Watanabe KA, Goldstein BM. Crystallographic studies of two alcohol dehydrogenase-bound analogues of thiazole-4-carboxamide adenine dinucleotide (TAD), the active anabolite of the antitumor agent tiazofurin. Biochemistry. 1994 Jan 11; 33(1):23-32.
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Zatorski A, Lipka P, Mollova N, Schram KH, Goldstein BM, Watanabe KA, Pankiewicz KW. Synthesis of thiazole-4-carboxamide-adenine difluoromethylenediphosphonates substituted with fluorine at C-2' of the adenosine. Carbohydr Res. 1993 Oct 18; 249(1):95-108.
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Li H, Kennedy SD, Goldstein BM. Solid-state and solution conformations of isotiazofurin: crystallographic, computational and 1H NMR studies. Acta Crystallogr B. 1993 Aug 1; 49 ( Pt 4):729-38.
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Burling FT, Goldstein BM. A database study of nonbonded intramolecular sulfur-nucleophile contacts. Acta Crystallogr B. 1993 Aug 1; 49 ( Pt 4):738-44.
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Pankiewicz KW, Zeidler J, Ciszewski LA, Bell JE, Goldstein BM, Jayaram HN, Watanabe KA. Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide. J Med Chem. 1993 Jun 25; 36(13):1855-9.
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Burling FT, Hallows WH, Phelan MJ, Gabrielsen B, Goldstein BM. Structures of the 4-cyano and 4-methylamidate analogs of tiazofurin. Acta Crystallogr B. 1992 Oct 1; 48 ( Pt 5):677-83.
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Li H, Goldstein BM. Carboxamide group conformation in the nicotinamide and thiazole-4-carboxamide rings: implications for enzyme binding. J Med Chem. 1992 Sep 18; 35(19):3560-7.
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Zhen W, Jayaram HN, Marquez VE, Goldstein BM, Cooney DA, Weber G. Cytotoxicity of tiazofurin and its arabinose and xylose analogues in K562 cells. Biochem Biophys Res Commun. 1991 Oct 31; 180(2):933-8.
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Goldstein BM, Leary JF, Farley BA, Marquez VE, Levy PC, Rowley PT. Induction of HL60 cell differentiation by tiazofurin and its analogues: characterization and efficacy. Blood. 1991 Aug 1; 78(3):593-8.
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Burling FT, Gabrielsen B, Goldstein BM. Structures of the 2',3'-dideoxy and 2',3'-didehydro-2',3'-dideoxy analogs of tiazofurin. Acta Crystallogr C. 1991 Jun 15; 47 ( Pt 6):1272-5.
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Goldstein BM, Bell JE, Marquez VE. Dehydrogenase binding by tiazofurin anabolites. J Med Chem. 1990 Apr; 33(4):1123-7.
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Tseng CK, Marquez VE, Fuller RW, Goldstein BM, Haines DR, McPherson H, Parsons JL, Shannon WM, Arnett G, Hollingshead M, et al. Synthesis of 3-deazaneplanocin A, a powerful inhibitor of S-adenosylhomocysteine hydrolase with potent and selective in vitro and in vivo antiviral activities. J Med Chem. 1989 Jul; 32(7):1442-6.
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Goldstein BM, Mao DT, Marquez VE. Ara-tiazofurin: conservation of structural features in an unusual thiazole nucleoside. J Med Chem. 1988 May; 31(5):1026-31.
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Banerjee A, Levy HR, Levy GC, LiMuti C, Goldstein BM, Bell JE. A transfer nuclear Overhauser effect study of coenzyme binding to distinct sites in binary and ternary complexes in glutamate dehydrogenase. Biochemistry. 1987 Dec 15; 26(25):8443-50.
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Takusagawa F, Goldstein BM, Youngster S, Jones RA, Berman HM. Crystallization and preliminary X-ray study of a complex between d(ATGCAT) and actinomycin D. J Biol Chem. 1984 Apr 25; 259(8):4714-5.
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