Actividades de investigación

Interests

Our scientific interest is centered on the understanding of protein function at the molecular level. At this particular level, a critical element to success is the combination of several disciplines. Our work lies on the interface between biology, chemistry and physics, looking at proteins as moderately flexible three-dimensional objects. The macromolecules' spatial structures and dynamics, place particular sets of chemically reactive atoms in the correct way, allowing them to perform an astonishing diversity of binding and catalytic functions in the cells.

Protein structures at atomic resolution give us unique insights into their functional mechanisms. X-ray crystallography is one of the most powerful approaches to determine such structures. Hence, protein crystallography in combination with biochemistry and molecular biology constitute the core of our experimental methods. Special attention is given to the study of carbohydrate processing enzymes (glycosyltransferases and glycosidases) and to the allosteric phenomena underlying signal transduction pathways in bacterial and eukaryotic cells.

Apart from the unraveling of carbohydrate active enzyme mechanisms (Watts et al. 2006 J. Biol. Chem., 281:4149-55) and ligand binding bases (Buschiazzo et al. 2004 EMBO J., 23: 3196-205), we are actively involved in the study of signal transduction and transcriptional regulation in bacteria (Albanesi et al. 2009 Proc. Natl. Acad. Sci. USA, 106:16185-90), as well as in trypanosomatidae parasites (Leishmania spp.).

Publications

• Albanesi D, Martín M, Trajtenberg F, Mansilla MC, Haouz A, Alzari PM, de Mendoza D, Buschiazzo A. Structural plasticity and catalysis regulation of a thermosensor histidine kinase. (2009) Proc Natl Acad Sci U S A 106:16185-90.
• Patenaude AM, Orthwein A, Hu Y, Campo VA, Kavli B, Buschiazzo A, Di Noia JM. Active nuclear import and cytoplasmic retention of activation-induced deaminase. (2009) Nat Struct Mol Biol 16:517-27.
• Neres J, Brewer ML, Ratier L, Botti H, Buschiazzo A, Edwards PN, Mortenson PN, Charlton MH, Alzari PM, Frasch AC, Bryce RA, Douglas KT. Discovery of novel inhibitors of Trypanosoma cruzi trans-sialidase from in silico screening. (2009) Bioorg Med Chem Lett 19:589-96.
• Buschiazzo A, Alzari PM. Structural insights into sialic acid enzymology. (2008) Curr Opin Chem Biol 12:565-72.
• Buchini S, Buschiazzo A, Withers SG. A new generation of specific Trypanosoma cruzi trans-sialidase inhibitors. (2008) Angew Chem Int Ed Engl 47:2700-3.
• Damager I, Buchini S, Amaya MF, Buschiazzo A, Alzari P, Frasch AC, Watts A, Withers SG. Kinetic and mechanistic analysis of Trypanosoma cruzi trans-sialidase reveals a classical ping-pong mechanism with acid/base catalysis. (2008) Biochemistry 47:3507-12.

Projects

-Signal transduction in eukaryotic systems: Structural Biology of protein kinases from Leishmania spp.

-Signal transduction in prokaryotic systems: procariotas: Structural Biology of two-component systems and transcription factors.

-Signal transduction in the regulation of lipid metabolism in Gram+ bacteria. Colaboration with Pedro M Alzari / Michael Nilges (IP – Paris, France) and Diego de Mendoza  (IBR, CONICET - Rosario, Argentina)

-Structural and mechanistic studies of trypanosomal sialidases.

-Structural studies of monoclonal antibodies that inhibit the trans-sialidase from Trypanosoma cruzi. Colaboration with Oscar Campetella (IIB, UNSAM - San Martín, Argentina)

Funding

• Molecular mechanisms of signaling in fatty acid synthesis of Gram-positive bacteria. 

Role : Principal Investigator
French National Research Agency (« Agence National de la Recherche ») 2007-2010.

• Estudios estructurales del mecanismo de transducción de señales en bacterias Gram+.

Role : Principal Investigator
National Research and Innovation Agency - Uruguay (“Agencia Nacional de Investigacion e Innovacion”) 2009-2010.

• Targeting the Leishmania kinome for the development of novel anti-parasitic strategies.

Role : Collaborative Partner Investigator 

European Union Framework Programme 7 - Collaborative Project - 2009-2011

• Signaling mechanisms controlling membrane fluidity in bacteria.

Role : Collaborative Partner Investigator

Agencia Nacional de Promoción Científica y Tecnológica (Argentina) - Cooperación Internacional Programa Raices 2007-2010

• Virulence factors in the pathogenesis of Chagas disease.

Role : Associate Investigator (Principal Investigator: Oscar Campetella)

Nacional Institutes of Health (USA) R01 2008-2011