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Dr Alexander Wlodawer
Macromolecular Crystallography Laboratory
NCI-Frederick
P.O. Box B, Frederick, MD 21702, USA
Email: wlodawer@ncifcrf.gov
Tel: +1-301-846-5036
Fax: +1-301-846-6322
Homepage: http://mcl1.ncifcrf.gov/wlodawer.html

Research
Crystallographic studies of proteases have been for us an important area of research since 1987. We have been particularly active in the investigation of structure-function relationship in aspartic proteases, including clinically important retroviral enzymes. Our studies of HIV protease, although no longer a major target of active research, are still ongoing and concentrate on the investigation of drug-resistant variants and their complexes with inhibitors. We have investigated retroviral proteases from several other sources, such as FIV, EIAV, and RSV and are actively investigating other retroviral enzymes. A complex of proteinase A with its specific protein inhibitor has established this enzyme as a chaperone for its own inhibition and provided the first glimpse of a helical inhibitor of aspartic proteases. We have an extensive program of investigating serine-carboxyl peptidases (sedolisins), a family that was first characterized based on crystal structures solved in this laboratory and that is found in many different organisms. The studies of TEV protease have elucidated the basis for the substrate specificity of this enzyme that is widely used in protein engineering. We are also investigating a bacterial ATP-dependent protease Lon, finding that is proteolytic domain has a unique fold and thus establishes a new family of proteases with a Ser-Lys catalytic dyad.
Collaborations
Ben Dunn, Ph.D.-University of Florida, Gainesville, FL

John Elder, Ph.D.-Scripps Research Institute, La Jolla, CA

Toru Nakamura, Ph. D.-Tohoku University, Sendai, Japan

Kohei Oda, Ph.D.-Kyoto Institute of Technology, Kyoto, Japan

Tatyana Rotanova, D.Sc.-Shemyakin and Ovchinnikov Institute, Moscow, Russia
Publications
M. Li, G.M. Morris, T. Lee, G.S. Laco, C-H. Wong, A.J. Olson, J.H. Elder, A. Wlodawer and A. Gustchina (2000) Structural studies of FIV and HIV-1 proteases complexed with an efficient inhibitor of FIV protease, Proteins: Structure, Function and Genetics, 38, 29-40.

M. Li, L.H. Phylip, W.E. Lees, J.R. Winther, B.M. Dunn, A. Wlodawer, J. Kay and A. Gustchina (2000) The aspartic proteinase from S. cerevisiae folds its own inhibitor into a helix, Nature Struct. Biol. 7, 113-117.

A. Wlodawer, M. Li, Z. Dauter, A. Gustchina, K. Uchida, H. Oyama, B. M. Dunn, and K. Oda (2001) Carboxyl proteinase from Pseudomonas defines a novel family of subtilisin-like enzymes, Nature Struct. Biol. 8, 442-446.

J. Phan, A. Zdanov, A. G. Evdokimov, J. E. Tropea, H. K. Peters III, R. B. Kapust, M. Li, A. Wlodawer and D. S. Waugh (2002) Structural basis for the substrate specificity of tobacco etch virus protease, J. Biol. Chem. 277, 50564-50472.

I. Botos, E. E. Melnikov, S. Cherry, J. E. Tropea, A. G. Khalatova, F. Rasulova, Z. Dauter, M. R. Maurizi, T. V. Rotanova, A. Wlodawer and A. Gustchina (2004) The catalytic domain of E. coli Lon protease has a unique fold and a Ser-Lys dyad in the active site, J. Biol. Chem., in press.





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