Prof. Ben M. Dunn

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University of Florida
College of Medicine
Biochemistry and Molecular Biology Department
Distinguished ProfessorAppointed: 1998

Mailing Address

Biochemistry & Molecular Biology
P.O. Box 100245
University of Florida College of Medicine
Gainesville, Florida 32610-0245
United States

Contact Information

Phone: (352) 392-3362
Fax: (352) 846-0412
bdunn@ufl.edu

Qualifications

Ph.D..

Expertise and Research Interests

Current research interests include studies of protein structure/function relationships, particularly involving proteolytic enzyme specificity. We use site-directed mutagenesis, protein expression and purification, enzyme kinetics, and x-ray crystallography to answer specific questions relating to defining critical active site interaction that lead to specific binding and efficient catalysis. These studies lead to new information of use in drug discovery programs.

Enzymes currently under study include: the HIV-1 protease; HTLV-1 protease; Feline Immunodeficiency Virus (FIV) protease; digestive enzymes from the mararia parasite, Plasmodium falciparum; fungal enzymes such as Candida albicans SAPs; human cathepsin D and human cathepsin E; the secreted serine proteases of certain species of pseudomonas and other bacteria as well as human CLN2; and plant proteases, including Arabadopsis thaliana.

Our work is based on knowledge of the three-dimensional structures of most of these enzymes, and we have established the capacity to produce pure proteins and crystals for new structure determination and have solved several structures of HIV-1 protease in complex with clinically-approved inhibitors. We have also obtained crystals of plasmepsins from P. falciparum, which are new targets for drug discovery.

Other Expertise

Protein Structure Prediction
Modeling of Proteins and Studies of Interactions
Council, American Peptide Society, 2002-2004, Chair, Membership Comm.
Secretary, International Proteolysis Society
Member, AARR3 Study Section, NIAID, NIH
Chair, Biophysical, Chemical, and Biochemical Sciences Fellowships, Panel, NIH
American Peptide Society, Council Member, 2001-2007
International Proteolysis Society, President, 2003-2005

Future Research

My laboratory focuses on the structure and mechanism of proteolytic enzymes, specifically aspartic proteinases as well as serine proteases. We have cloned a number of enzymes from mammalian, fungal, viral, and protozoan sources and are expressing these in bacteria. We deal with protein folding problems in order to optimize the yield of active proteases. We are constructing chimeric enzymes by mixing N- and C-terminal domains from different aspartic proteinases. We have devised new oligopeptide substrates for the detailed analysis of the activity of native and recombinant enzymes. We are using combinatorial libraries to study substrate specificity across the aspartic proteinase family. We are also extending this analysis to some serine proteinases from bacteria and from mammals. We work with both synthetic small molecule inhibitors and protein inhibitors. The latter are produced in recombinant form. We have several collaborations with crystallographers and have published our work on several systems. We have established crystallography at the University of Florida in order to continue our studies of structure and function and have published on structures of HIV-1 protease in complex with inhibitors.

Industrial Relevance

Our work is related to the objective of the design of potent and selective inhibitors of enzymes that might be developed as drugs targeted against pathogenic organisms. The organisms include viruses (HIV, HTLV-1, and FIV), protozoa (Plasmodium sp.), tuberculosis bacteria, and fungi (Candida sp.).

Keywords

COS Keywords:

AIDS, Biochemistry, Biochemistry, Proteins, Biophysics, Biotechnology, Computer Graphics, Crystallography, Drug Design, Enzymes, Enzymology, Infectious Diseases Or Agents, Molecular Biology, Mutagenesis, Parasitology, Peptides, Protein Engineering, Protein Structure.

Additional Terms:

Aspartyl Proteases, Enzyme Kinetics, Enzyme Mechanisms/Catalysis, Molecular Enzymology, Peptide Hormones, Peptide Synthesis, Protease Inhibitors, Protein Chemistry, Protein Conformation, Protein Engineering, Protein Sequence Analysis.

Languages

(Reading, Writing, Speaking)

German: (Functional, Basic, Basic)

Memberships

American Association for the Advancement of Science
American Peptide Society
American Society for Biochemistry and Molecular Biology
International Proteolysis Society
Protein Society

Honors and Awards

2007-2011, Board of Directors, FASEB
2005-2010, MERIT Award, National Institutes of Health (NIH), HIV Protease
1999-2001, Research Foundation Professorship University of Florida, Protein Engineering
1998, Distinguished Professor University of Florida, Protein Chemistry & Enzymology
1996, Professorial Excellence Program Award University of Florida, Proteolytic Enzymes
1994, Chair, Gordon Research Conference, Gordon Research Conferences, Proteolytic Enzymes and Their Inhibitors
1994, Faculty Research Prize, College of Medicine, University of Florida, Enzymology of HIV Protease
1989, Faculty Research Award, Sigma Xi, University of Florida, Proteolytic Enzymes
1983, American Men and Women of Science, University of Florida, Protein Chemistry
1977-1982, Research Career Development Award, National Institutes of Health, University of Florida, Enzymology
1971-1973, NIH Postdoctoral Fellowship National Institutes of Health, Bethesda, Protein Chemistry & Enzymology
1968-1971, NIH Predoctoral Fellowship, National Institutes of Health, University of California, Santa Barbara, BioOrganic Chemistry

Previous Positions

1986-1998, Professor, University of Florida, College of Medicine, Biochemistry and Molecular Biology Department
1980-1985, Associate Professor, University of Florida, College of Medicine, Biochemistry and Molecular Biology Department
1974-1979, Assistant Professor, University of Florida, College of Medicine, Biochemistry and Molecular Biology Department
1973-1974, Staff Fellow, National Institute of Health (NIH)
1971-1973, Postdoctoral Fellow, National Institute of Health (NIH)

Funding Received

  • Role: PI: Human Immunodeficiency Virus Proteinase, $1,118,507, Sept 1, 2001 to Jun 30, 2005.
  • Role: PI: Mechanisms of Pepsin Catalysis and Inhibition, $678,456, Jan 15, 1997 to Dec 31, 2002.
  • National Institutes of Health (NIH): Novel Inhibitors of Fungal Proteinases, $450,000, Jan 1, 2000 to Dec 30, 2003.
  • Role: Co-PI: Plasmepsins as AntiMalarial Drug Targets, $263,240 (DUNN), Feb 1, 1996 to Jan 31, 2000.

Publications

  • Pettit SC, Everitt LE, Choudhury S, Dunn BM, Kaplan AH, Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism, Journal of Virology, 78(16), 8477-85, August 2004 Abstract
  • Green TB, Ganesh O, Perry K, Smith L, Phylip LH, Logan TM, Hagen SJ, Dunn BM, Edison AS, IA3, an aspartic proteinase inhibitor from Saccharomyces cerevisiae, is intrinsically unstructured in solution, Biochemistry, 43(14), 4071-81, April 2004 Abstract
  • Wlodawer A, Li M, Gustchina A, Oyama H, Oda K, Beyer BB, Clemente J, Dunn BM, Two inhibitor molecules bound in the active site of Pseudomonas sedolisin: a model for the bi-product complex following cleavage of a peptide substrate, Biochemical and Biophysical Research Communications, 314(2), 638-45, February 2004 Abstract
  • Clemente JC, Hemrajani R, Blum LE, Goodenow MM, Dunn BM, Secondary mutations M36I and A71V in the human immunodeficiency virus type 1 protease can provide an advantage for the emergence of the primary mutation D30N, Biochemistry, 42(51), 15029-35, December 2003 Abstract
  • Alex Wlodawer, Mi Li, Alla Gustchina, Hiroshi Oyama, Ben M. Dunn, and Kohei Oda, Structure and enzymatic properties of the sedolisin family of serine-carboxyl peptidases, Acta Biochimica Polonica, 50(1), 81-102, 2003
  • M. Comellas-Bigler, P. Fuentes-Prior, K. Maskos, R.O. Huber, H. Oyama, K. Uchida, B.M. Dunn, K. Oda and W. Bode, The 1.4 Ang Crystal Structure of Kumamolysin, a Thermostabel Serine-Carboxyl Type Peptidase, Structure, June 2002
  • Ben M. Dunn, Maureen M. Goodenow, A. Gustchina, and Alex Wlodawer, Retroviral proteases, Genome Biology, 3(4), 3006.1-3006.7, 26 Mar 2002
  • H. Oyama, T. Hamada, S. Ogasawara, K. Uchida, S. Murao, B.B. Beyer, B.M. Dunn and K. Oda, A CLN2-Related and Thermostable Serine-Carboxyl Proteinase, Kumamolysin: Cloning, Expression, and Identification of Catalytic Serine Residue, Journal of Biochemistry (Tokyo), 131(5), 757-765, 2002
  • M.M. Goodenow, G.Bloom, S.L. Rose, S.M. Pomeroy, P.O. O'Brien, E.E. Perez, J.W. Sleasman and B.M. Dunn, Naturally-Occurring Amino Acid Polymorphisms in Human Immunodeficiency Virus Type 1 (HIV-1) Gag p7(NC) and the C-Cleavage Site Impact Gag-Pol Processing by HIV-1 Protease, Virology, 292, 137-149, 2002
  • Ben M. Dunn, Anatomy and pathology of HIV-1 protease, Essays in Biochemistry, 38, 113-127, 2002
  • A. Wlodawer, M. Li, A. Gustchina, Z. Dauter, K. Uchida, H. Oyama, K. Oda, N. Goldfarb, and B. M. Dunn, Inhibitor complexes of the Pseudomonas serine-carboxyl proteinase, Biochemistry, 40(51), 15602-15611, December 2001
  • Wlodawer A, Li M, Dauter Z, Gustchina A, Uchida K, Oyama H, Dunn BM, Oda K, Carboxyl proteinase from Pseudomonas defines a novel family of subtilisin-like enzymes, Nature Structural Biology, 8(5), 442-6, May 2001 Abstract
  • E.E. Perez, S.L. Rose, B. Peyser, S.L. Lamers, B. Burkhardt, B.M. Dunn, A.D. Hutson, J.W. Sleasman and M.M. Goodenow, Human Immunodeficiency Virus Type 1 Protease Genotype Predicts Immune and Viral Responses to Combination Therapy with Protease Inhibitors (PIs) in PI-Naive Patients, Journal of Infectious Diseases, 183, 579-588, 2001
  • Ng KK, Petersen JF, Cherney MM, Garen C, Zalatoris JJ, Rao-Naik C, Dunn BM, Martzen MR, Peanasky RJ, James MN, Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3, Nature Structural Biology, 7(8), 653-7, August 2000 Abstract
  • Li M, Phylip LH, Lees WE, Winther JR, Dunn BM, Wlodawer A, Kay J, Gustchina A, The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor into a helix, Nature Structural Biology, 7(2), 113-7, February 2000 Abstract
  • Westling J, Cipullo P, Hung SH, Saft H, Dame JB, Dunn BM, Active site specificity of plasmepsin II, Protein Science, 8(10), 2001-9, October 1999
  • Dunn BM, Pennington MW, Frase DC, Nash K, Comparison of inhibitor binding to feline and human immunodeficiency virus proteases: Structure-based drug design and the resistance problem, Biopolymers, 51(1), 69-77, 1999

Profile Details

Last Updated: 3/4/2008

COS Expertise ID #401891
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