INSTITUTO DE QUIMICA, FISICA DE LOS MATERIALES, MEDIOAMBIENTE Y ENERGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Structural basis for ligand recognition in a mushroom lectin: Solvent structure as specificity predictor
DIEGO F GAUTO, SANTIAGO DI LELLA, DARIO A ESTRIN, HUGO L. MONACO AND MARCELO A. MARTDIEGO F GAUTO, SANTIAGO DI LELLA, DARIO A ESTRIN, HUGO L. MONACO AND MARCELO A. MART
Buenos Aires, Argentina
Congreso; Primer Congreso Argentino de Bioinformatica y Biologia Computacional; 2010
Structural basis for ligand recognition in a mushroom lectin: Solvent structure as specificity predictor Diego F Gauto,1 Santiago Di Lella,1 Dario A Estrin,1 Hugo L Monaco3 and Marcelo A. Marti1,2 1 Departamento de Química Inorgánica, Analítica, y Química Física, INQUIMAE-CONICET. 2 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, C1428EHA Ciudad de Buenos Aires, Argentina. 3 Biocrystallography Laboratory - Department of Biotechnology, University of Verona, Strada Le Grazie, 15, 37134 Verona, Italy. To whom correspondence should be addressed : firstname.lastname@example.org or email@example.com Context Lectins are widely distributed proteins able to recognize specific carbohydrate structures. Key elements of their biological role are the specificity by which the carbohydrate recognition domain (CRD) binds a given saccharide. The lectin from mushroom Agaricus bisporus (ABL) has the remarkable ability of selectively recognizing the T-antigen, an important malignancy marker, composed of Galβ1-3GalNac, Ser/Thr linked to proteins which is specifically exposed in neoplastic tissues. Binding of the lectin initiates receptor-mediated endocytosis inhibiting malignant cell line proliferation. Motivation Strikingly, the recently solved crystal structure of tetrameric ABL in the presence of T-Antigen and other carbohydrates showed that each monomer has two CRDs, each being able to bind specifically to different monosaccharides that can differ only in the configuration of a single epimeric hydroxyl like N-Acetyl-Galactosamine (NGA) and N-Acetyl-Glucosamine (NAG). (1) The way that lectin CRDs bind and discriminate different mono and/or (poly)-saccharides is one of the most important yet unresolved issued in glycobiology and understanding the molecular and structural basis of lectin carbohydrate interaction may result in the design of better and selective lectin inhibitors with potential therapeutic properties. Methodology In this work, and based on the unusual monosaccharide epimeric specificity of the ABL CRDs (REF), we have performed MD simulations of the natural (crystallographic) and inverted (changing NGA for NAG and vice-versa) ABL-monosaccharide complexes in order to understand the selective ligand recognition properties of each CRD. We also performed a detailed analysis of the CRD local solvent structure, using previous developed methodology (2, 3), and related it with the recognition mechanism. Conclusion Our results provide a detailed and semi-quantitative picture of each CRD epimeric specifity allowing a better understanding of the carbohydrate selective recognition process in lectins, that includes solvent structural analysis. Reference 1. Carrizo, M. E., Capaldi, S., Perduca, M., Irazoqui, F. J., Nores, G. A. & Monaco, H. L. (2005) J Biol Chem 280, 10614-23. 2. Di Lella, S., Marti, M. A., Alvarez, R. M. S., Estrin, D. A. & Díaz Ricci, J. C. (2007) J Phys Chem B 111, 7360-7366. 3. Gauto, D. F., Di Lella, S., Guardia, C. M., Estrin, D. A. & Marti, M. A. (2009) J Phys Chem B 113, 8717-24. Acknowledgment Computer power was partially provided by CECAR at FCEN-UBA. This work was supported by Grants from the Argentinean National Agency for the Promotion of Science and Technology PICT 2007-01650 to MAM and PICT 2007-0157 to DAE, from the University of Buenos Aires UBA08-X625 to M.A.M, and CONICET-PIP2009 and UBA to DAE. DFG and SDL are grateful to CONICET for a Doctoral and post-doctoral fellowships respectively. MAM and DAE are staff members of CONICET.