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. He is a member of the American Crystallographic Association and the Protein Society and was an elected officer in both organizations.

Research

We are investigating the relationship between protein structure and function, mainly by the technique of high-resolution X-ray diffraction. In the past several years, our work has concentrated in three distinct areas.

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 retroviral proteases from several other sources such as FIV, RSV, and HTLV. 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. Cockroach allergen Bla g 2 was shown to be an inactive aspartic protease. 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 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.

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 established that a helical cytokine, interleukin-10 (IL-10), is a domain-swapped dimer in which each compact half is composed of fragments of two identical molecules. The structure of a related cytokine encoded in the genome of Epstein-Barr virus has now been determined, providing the first glimpse of the molecular architecture of an agent used by the virus to control the host's immune system. We also solved the crystal structure of IL-19. We have purified and crystallized complexes of IL-10 with its specific receptor and are studying complexes of several other cytokines related to IL-10, such as IL-19, IL-20, and IL-22. We are also investigating IL-15 in complex with its receptor sushi domain.

Proteins involved in ribosome biogenesis and RNA interference

Two related serine protein kinases, Rio1 and Rio2, are involved in processing 20S pre-RNA to 18S ribosomal RNA. Their crystal structures, solved by our Section, established that they belong to a novel family of kinases with a truncated substrate-binding region, although they are capable of both self- and trans-phosphorylation. We are currently investigating their catalytic properties and a potential biological role. We are also working on structural studies of Dicer, an enzyme crucial in the RNA interference pathway.

Our collaborators include Anna Marie Skalka, Ph.D., Fox Chase Cancer Center; Jonathan Leis, Ph.D., Northwestern University; John Kay, Ph.D., University of Cardiff; Ben Dunn, Ph.D., University of Florida; John Elder, Ph.D., The Scripps Research Institute; Kohei Oda, Ph.D., Kyoto Institute of Technology; and Witold Filipowicz, M.D., Friedrich Miescher-Institut, Basel, Switzerland.

This page was last updated on 6/12/2008.