Federal Fluminense University, Brazil
Title: Looking for β3 integrin family selectivity: The use of snake venom disintegrin as a tool for molecular modeling approach
Reinaldo Barros Geraldo is a young scientist, researcher currently postdoc at Fluminense Federal University (Brazil). Graduated in Biomedicine Fluminense Federal University (2007), Master of Neuroimmunology, Fluminense Federal University (2009) and Doctor of Science by Federal University of Rio de Janeiro (2013). Has experience in the areas of biochemistry, with an emphasis on computer modeling, acting on the following subjects: Comparative modeling, structural biochemistry and Molecular Biology. At now, he has published 11 papers in reputed journals.
Disintegrins are a family of modulatory peptides that inhibit the some integrins, such as αIIbβ3 and αvβ3, which are involved in a variety of cellular functions such as platelet aggregation and angiogenesis, physiopathology of arterial thrombosis and cancer. These disintegrins were identified several sources including venom of some snakes. The aims of this study were to analyze using in silico approaches (i.e. molecular modeling and molecular dynamics) this disintegrin sub-family, to observe the selectivity against those integrins. In addition, perform a study of molecular biology with two disintegrins present in the venom of Bothrops jararaca venom, jararacin and jarastatin, to use these disintegrins as a model for study of new prototype of new drugs against those pathologies. The in silico analyses of 70 snake venoms disintegrins showed with the alignment and phylogeny results, the presence of four distinct sub-groups that possess the high similarity among them. From those subgroups, we select two disintegrins of these four sub-groups: sub-group 1 (albolatin and mojastin), sub-group 2 (jarastatin and salmosin) sub-group 3 (trimestatin and flavoridin) group 4 (kistrin and jararacin), and whose were used to construct the complexes with integrins αIIbβ3, αvβ3 and α5β1. These complexes were minimized with the GROMACS program. Moreover, the interaction of them was analyzed with the webservers PISA, protein interaction calculator (PIC) and GROMACS program. The analysis of the complexes with α5β1, the sub-group 1 and sub-group 3 and kistrin present the number of interations is greater than others. The αIIbβ3 complexes show the jararacin, sub-group 1 and sub-group 3 present the number of interactions is greater than the sub-group 2 and kistrin. And the αvβ3 complexes show sub-group 2 with the high interactions values than others followed by sub-group 3 and sub-group 1. The molecular dynamics reveals corroborated the initial in silico results that shows jararacin to αIIbβ3 complex formation and jarastatin possess more stability of αvβ3 complex formation. This study shows the presence of subgroups in the PII-disintegrins, and they present a different selectivity against integrins. We succeeded in producing recombinant disintegrins of Bothrops jararaca with the maintenance of biological activity.
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