Our Science – Wlodawer Website

Alexander Wlodawer, Ph.D.

Macromolecular Crystallography Laboratory Head, Protein Structure Section Laboratory Chief Building 536 Room 5 Frederick, MD 21702-1201 Phone:   301-846-5036 Fax:   301-846-6322 E-Mail:   wlodawer@ncifcrf.gov Link: Other Homepage

Biography

Dr. Wlodawer received his Ph.D. from the University of California, Los Angeles, in 1974. Having completed his postdoctoral training at Stanford University, he joined the National Bureau of Standards in 1976, then moved to the ABL-Basic Research Program at the NCI-FCRDC in 1987. From October 1998 to March 1999, he was on sabbatical as an elected Visiting Fellow of Sidney Sussex College, University of Cambridge. In 1999, Dr. Wlodawer was appointed Chief of the Macromolecular Crystallography Laboratory, CCR, NCI. Dr. Wlodawer is an Adjunct Professor in the George Washington University Institute of Biomedical Sciences and Doctor Honoris Causa of the Technical University of Lodz, Poland. He was elected Foreign Member of the Polish Academy of Sciences in 2005, is a recipient of the 2006 NCI Mentor of Merit Award, and was awarded the Heyrovsky Honorary Medal by the Czech Academy of Sciences in 2008. He is a member of the American Crystallographic Association and of the Protein Society and was an elected officer in both organizations. Since 2007 he serves as an Editor of the FEBS Journal.

Research

Our Section investigates the relationship between protein structure and function, mainly by the technique of high-resolution X-ray diffraction. Some of the areas of interest are directly involved in elucidating structural features of the molecules that could explain their importance to understanding cancer and AIDS, but we are also active in the development of methods for protein crystallography.

Crystallographic studies of proteases

Crystallographic studies of proteases have been an important area of research of this Section since its establishment. 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 structure-function relationship in retroviral proteases from several other sources such as FIV, RSV, EIAV, and HTLV-1. Cockroach allergen Bla g 2 was shown to be an inactive aspartic protease and we solved its structure by itself, and in a complex with several specific antibodies. We have determined the structure of a unique histoaspartic protease, an enzyme with the pepsin fold, but a vastly different mechanism. We found that Shigella virulence factor VirA is a putative protease with a novel fold, and we are examining its structural and enzymatic properties. We have established 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. We are also investigating the bacterial ATP-dependent protease Lon, having found that its proteolytic domain has a unique fold and thus establishes a new family of proteases with a Ser-Lys catalytic dyad. We have solved the structures of the proteolytic domain of A and B type Lon proteases, encoded by E. coli and Archaeoglobus fulgidus, as well as the N-terminal and α domains of E. coli Lon.

Cytokines and cytokine receptors

Our Section has been investigating the crystal structures of several cytokines and has made progress in preparing their receptor complexes. We have purified and crystallized complexes of IL-10 with its specific receptor, solved the structure of IL-19, and are studying complexes of several cytokines related to IL-10, such as IL-19, IL-20, IL-22, IFN-λ1 and IFN-λ2.
Proteins involved in ribosome biogenesis and RNA interference

Lectins with Antiviral Activity

We have been involved in studies of several lectins with antiviral activities, some of them used in pre-clinical trials as potential drugs preventing HIV infection. We have solved the structure of griffithsin, as free protein and complexed with a number of mono- and disaccharides, explaining the structural basis for its tight binding to branched mannose-rich carbohydrates. We have reengineered griffithsin into a monomeric form and determined its structure in complex with branched carbohydrates. We have also solved the structure of another lectin, scytovirin, and are investigating its mode of carbohydrate binding.

Our extramural collaborators include Anna Marie Skalka, Ph.D., Fox Chase Cancer Center; Ben Dunn, Ph.D., University of Florida; John Elder, Ph.D., The Scripps Research Institute; Rickey Yada, Ph.D., University of Guelph, Guelph, Canada; Mariusz Jaskolski, D.Sc., Adam Mickiewicz University, Poznan, Poland; and Tatyana Rotanova, D.Sc., Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.

This page was last updated on 9/4/2009.