Immunology, Transplantation and Infectious diseases
Biocrystallography
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.
Research activity
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.
Degano, M – Structure, oligomerization and activity modulation in N-ribohydrolases (2022) Int J Mol Sci 23: 2576. doi: 10.3390/ijms23052576
Gemenetzi K, Psomopoulos F, Carriles A, Gounari M, Minici C, Plevova K, Sutton L, Tsagiopoulou M, Pasentsis K, Anagnostopoulos, Sandaltzopoulos R, Rosenquist R, Davi F, Pospisilova S, Ghia P, Stamatopoulos K, Degano M*, Chazidimitrou A* – Higher order immunoglobulin repertoire restrictions in CLL: the illustrative case of stereotyped subsets #2 and #169 (2021) Blood 137:1895-1904. doi: 10.1182/blood.2020005216
Minici C, Mosca L, Ilisso CP, Cacciapuoti G, Porcelli M, Degano M – Structures of catalytic cycle intermediates of the Pyrococcus furiosus methionine adenosyltransferase demonstrate negative cooperativity in the archaeal orthologues (2020) J Struc Biol 18: 107462, doi:10.1016/j.jsb.2020.107462
Patrone M, Cammarota E, Berno V, Tornaghi P, Mazza D, Degano M – Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor (2020) Commun Biol 3: 27, doi:10.1038/s42003-020-0752-4
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.
Gangemi F, Degano M – Disease-associated mutations in the coil 2B domain of human lamin A/C affect structural properties that mediate dimerization and intermediate filament formation. (2013) J Struc Biol 181, 17-28, doi: 10.1016/j.jsb.2012.10.016
Vavassori S, Cortini M, Masui S, Sannino S, Anelli T, Caserta IR, Fagioli C, Mossuto MF, Fornili A, van Anken E, Degano M, Inaba K, Sitia R – A pH-regulated quality control cycle for surveillance of secretory protein assembly. (2013) Mol Cell 50, 783-792, doi: 10.1016/j.molcel.2013.04.016.
Fornili A, Giabbai B, Garau G, Degano M – Energy landscapes associated with macromolecular conformational changes from endpoint structures. (2010) J Am Chem Soc 132, 17570-17577
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.
Grant EP, Degano M, Rosat JP, Stenger S, Modlin RL, Wilson IA, Porcelli SP, Brenner MB – Molecular recognition of lipid antigens by T cell receptors. (1999) J Exp Med 189, 195-205
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.
