2001 - Center for Advanced Biotechnology and Medicine - Rutgers ...

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approach is the expression of recombinant turkey OM3D in E. coli and specific mutagenesis of reactive site residues. Mutant inhibitors are then tested for binding affinity with a panel of serine _____________________________________________________________ Stephen Anderson proteases. Our goal is to provide a complete, canonical set of ovomucoid third domain (OM3D) variants with every amino acid at the reactive site mutagenized, individually, to every other amino acid. This project is virtually complete, with the last mutants currently being made. The work is being conducted in collaboration with Dr. Michael Laskowski Jr.’s laboratory at Purdue University and Dr. Michael James’ laboratory at Edmonton, Alberta. The resultant database will represent an unparalleled resource for drug design groups and other users interested in rationalizing the energetics of protein-protein interactions. We also have a long-term effort aimed at developing improved industrial methods for synthesizing vitamin C. We are working on increasing the activity of a crucial enzyme in the pathway from glucose to 2-keto-L-gulonic acid [a precursor of vitamin C], 2,5-diketo-Dgluconic acid (2,5-DKG) reductase, using protein engineering techniques and extensive mutagenesis of the enzymes’ substrate and cofactor binding sites. Publications: Bateman, K. S., Anderson, S., Lu, W., Qasim, M. A., Laskowski Jr., M. L. and James, M. N. G. (2000). Deleterious effects of b-branched residues in the S1 specificity pocket of Streptomyces griseus proteinase B (SGPB), crystal structures of the turkey ovomucoid third domain variants Ile18I, Val18I, Thr18I, and Ser18I in complex with SGPB. Protein Sci., 9:83 - 94. Khurana, S., Powers, D. B., Anderson, S. and Blaber, M. (2000). Molecular dynamics of 2,5diketo-D-gluconic acid reductase A complexed with substrate. Proteins, Struct. Funct. & Genet., 39: 68-75. Bateman, K.S., Huang, K., Anderson, S., Lu,W., Qasim, M.A., Laskowski, M. Jr. and James, M.N. (2001). Contribution of peptide bonds to inhibitor-protease binding: crystal structures of the turkey ovomucoid third domain backbone variants OMTKY3-Pro18I and OMTKY3psi[COO]-leu18I in complex with Streptomuces griseus proteinase B (SGPB) and the structure of the free inhibitor, OMTKY-3-psi[CH2NH2+]-Asp19I. J. Mol. Biol. 305:839-49. __________________________________________________________________________________ Center for Advanced Biotechnology and Medicine 38
Arnold B. Rabson, M.D. Resident Faculty Member, CABM; Professor, UMDNJ-Robert Wood Johnson Medical School, Department of Molecular Genetics and Microbiology; Adjunct Professor, UMDNJ-RWJMS, Department of Pathology Viral Pathogenesis Laboratory Dr. Arnold Rabson joined CABM in the summer of 1990. Previously, he performed his residency in pathology at Brigham and Women’s Hospital in Boston. He was a medical staff fellow and a senior staff fellow in Malcolm Martin’s laboratory at the National Institute of Allergy and Infectious Diseases from 1981 to 1990. Dr. Rabson has served on a number of federal grant review boards, including an NIH Special Review Committee for AIDS. He is a member of the NIH Pathology B study section and has served as Chairman of several Special Emphasis Panels of the NIH Center for Scientific Review. He is on the editorial board of the Journal of Virology, Clinical Cancer Research and the Journal of Biomedical Science. Dr. Rabson is also the Associate Director for Basic Research of the Cancer Institute of New Jersey (CINJ) and directs the Transcriptional Regulation and Oncogenesis Program of CINJ. Dr. Rabson’s laboratory focuses on the molecular basis of cancer and human retroviruses. His research program encompasses studies of the viral and cellular mechanisms that regulate the expression of human retroviruses that cause cancer and AIDS, the human T-cell leukemia virus type 1 (HTLV-1) and the human immunodeficiency virus (HIV). A second aspect of the laboratory studies the roles of cellular transcription factors in the development and progression of human malignancies, including leukemia, lymphomas, and prostate cancer. Previous studies in Dr. Rabson's laboratory identified the frequent occurrence of molecular alterations in the gene encoding the NFKB2 transcription factor in the malignant cells of patients with cutaneous T-cell lymphoma (CTCL). Over the past year, Dr. Rabson’s laboratory has demonstrated that the tumor associated NF-κB-2 mutants also gain new gene regulatory functions. Regulated expression of these aberrant proteins can prevent T cell death and increase proliferation; thus the lymphoma associated rearrangements lead to both a loss of function and a gain of new transcriptional regulation. Dr. Rabson is now identifying the target genes of the tumor associated mutant proteins that may explain how this genetic alteration leads to T cell lymphomas. Dr. Rabson's laboratory has demonstrated inappropriate, constitutive, activation of NF-κB in a series of aggressive, tumorigenic, human prostate cancer cell lines and has shown inappropriate activation of NF-κB in focal areas of primary prostate cancer samples from patients with the disease. He has further shown that constitutive, inappropriate activation of NF-κB in the prostate cancer cells is due to activation of regulatory kinases such as the IkappaB kinases and the NF-κB kinase. He is continuing to study the consequences of NF-kB expression in prostate cancer cells. This work offers possible new approaches for therapy of the disease. __________________________________________________________________________________ Center for Advanced Biotechnology and Medicine 39
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