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. 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.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Mammalian Cell Lines Committee (MCL)
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Basic Sciences
United States
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Zdanov, Alexander (2010) Structural analysis of cytokines comprising the IL-10 family. Cytokine Growth Factor Rev :
Jaskolski, Mariusz; Gilski, Miroslaw; Dauter, Zbigniew et al. (2007) Stereochemical restraints revisited: how accurate are refinement targets and how much should protein structures be allowed to deviate from them? Acta Crystallogr D Biol Crystallogr 63:611-20
Demartini, Diogo Ribeiro; Wlodawer, Alexander; Carlini, Celia Regina (2007) A comparative study of the expression of serine proteinases in quiescent seeds and in developing Canavalia ensiformis plants. J Exp Bot 58:521-32
LaRonde-LeBlanc, Nicole; Santhanam, Arti N; Baker, Alyson R et al. (2007) Structural basis for inhibition of translation by the tumor suppressor Pdcd4. Mol Cell Biol 27:147-56
Sanches, Mario; Krauchenco, Sandra; Martins, Nadia H et al. (2007) Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development. J Mol Biol 369:1029-40
Wlodawer, Alexander (2007) Deposition of structural data redux. Acta Crystallogr D Biol Crystallogr 63:421-3
Xu, Qin; Guo, Hao-Bo; Wlodawer, Alexander et al. (2007) The QM/MM molecular dynamics and free energy simulations of the acylation reaction catalyzed by the serine-carboxyl peptidase kumamolisin-As. Biochemistry 46:3784-92
Botos, Istvan; Wlodawer, Alexander (2007) The expanding diversity of serine hydrolases. Curr Opin Struct Biol 17:683-90
Jaskolski, Mariusz; Li, Mi; Laco, Gary et al. (2006) Molecular replacement with pseudosymmetry and model dissimilarity: a case study. Acta Crystallogr D Biol Crystallogr 62:208-15
Rotanova, Tatyana V; Botos, Istvan; Melnikov, Edward E et al. (2006) Slicing a protease: structural features of the ATP-dependent Lon proteases gleaned from investigations of isolated domains. Protein Sci 15:1815-28

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