The activities in the Unit are aimed at clarifying the relationship between the function and the three-dimensional structure of biological macromolecules such as proteins, nucleic acids, polysaccharides, lipids, and their complexes.
The unit study macromolecules that are central in basic processes of cellular life, as well as for specific human pathologies. Starting from highly purified samples, researchers apply an array of biophysical techniques that include X-ray crystallography and cryo-electron microscopy to achieve high-resolution information on their structure. The structural analysis guides further mutagenesis and biochemical experiments in both reconstituted systems in vitro and in primary cells, to finely analyze the mechanisms that mediate macromolecular function, or lead to a pathological dysfunction. This multidisciplinary analysis provides the blueprint for a detailed understanding of complex biological processes, the pathogenic mechanisms leading to diseases such as cancer, autoimmune or genetic diseases. The high resolution structures are the starting point for the design of lead compounds that are endowed with high specificity, and can undergo further development for the design of highly specific, personalized drugs.
Current projects include the study of the molecular mechanism underlying the onset of Chronic Lymphocytic Leukemia, with the ultimate goal of developing compounds that antagonize the pathogenic B-cell receptor-mediated signal, specific for each subgroup of patients.
A second line of research focuses on the aspects of G- protein coupled receptor-mediated signals in the therapy of Multiple Sclerosis. The unit is studying the molecular aspects of the binding of fingolimod to the sphingosine 1-phosphate receptor family members, in order to fully appreciate the ligand features that induce the therapeutic effect.
Moreover, the unit is exploring the possibility to develop new ligands specific to orphan GPCRs to induce a remyelination process in damaged CNS and PNS.
Minici C, Gounari M, Übelhart R, Scarfò L, Dühren-von Minden M, Schneider D, Tasdogan A, Alkhatib A, Agathangelidis A, Ntoufa S, Chiorazzi N, Jumaa H, Stamatopoulos K, Ghia P, Degano M. Distinct homotypic B-cell receptor interaction shape the outcome of chronic lymphocytic leukaemia. Nat Commun 2017; 8, 15746.
Giannese F, Berg M, Van Der Veken P, Castagna V, Tornaghi P, Augustyns K, Degano M. Crystal structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals and a novel metalorganic inhibitor. Acta Cryst D Biol Crystallogr. 2013 Aug; 69(Pt 8):1553-66.
Vandemeulebroucke A, Minici C, Bruno I, Muzzolini L, Tornaghi P, Parkin DW, Versées W, Steyaert J, Degano M. Structure and mechanism of the 6- oxopurine nucleosidase from Trypanosoma brucei brucei. Biochemistry 2010 Oct 19;49(41):8999-9010.
Giabbai B, Sidobre S, Crispin MD, Sanchez-Ruiz Y, Bachi A, Kronenberg M, Wilson IA, Degano M. Crystal structure of mouse CD1d bound to the self ligand phosphatidylcholine: a molecular basis for NKT cell activation. J Immunol 2005 Jul;175(2):977-84.
Giabbai B, Degano M. Crystal structure to 1.7 Å of the Escherichia coli pyrimidine nucleoside hydrolase YeiK, a novel candidate for cancer gene therapy.Structure 2004 May;12(5):739-49.
Markovic-Housley Z, Degano M, Lamba D, von Roepenack-Lahaye E, Clemens S, Susani M, Ferreira F, Scheiner O, Breiteneder H. Crystal structure of a hypoallergenic isoform of the major birch pollen allergen Bet v 1 and its likely biological function as a plant steroid carrier. J Mol Biol. 2003 Jan;325(1):123-33.
Degano M, Garcia KC, Apostolopulos V, Rudolph MG, Teyton L, Wilson IA. A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 2000 Mar;12(3):251-61.
Wingren C, Crowley M, Degano M, Chien Y-S, Wilson IA. Crystal structure of a T cell receptor ligand T22: a truncatedMHC-like fold. Science 2000 Jan;287(5451):310- 314;
Garcia KC and Degano M, Pease LR, Huang M, Peterson PA, Teyton L, Wilson IA. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 1998 Feb;279(5354):1166-72.
Garcia KC, Degano M, Stanfield RL, Brunmark A, Jackson MR, Peterson PA, Teyton L, Wilson IA. An αβ T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 1996; 274(5285):209-219.