| Grant number: | 16/24191-8 |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| Start date: | June 01, 2017 |
| End date: | February 28, 2022 |
| Field of knowledge: | Biological Sciences - Biophysics - Molecular Biophysics |
| Agreement: | Coordination of Improvement of Higher Education Personnel (CAPES) |
| Principal Investigator: | Marcos Roberto de Mattos Fontes |
| Grantee: | Rafael Junqueira Borges |
| Host Institution: | Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil |
| Associated scholarship(s): | 17/13485-3 - Development and release of SEQUENCE SLIDER: a multi-side chain evaluator applied to toxinology and phasing, BE.EP.PD |
Abstract Most ophidian accidents in Latin America are caused by Bothrops genus snakes. Myonecrosis, which is not efficiently neutralized by antivenom treatment, is one of the consequences of these accidents. Myotoxic phospholipases A2-like (PLA2-like) proteins are usually abundant in bothropic venom and one of the main responsibles for muscular necrosis. PLA2-like proteins are myotoxic by breaking membrane integrity by a non-catalytic mechanism not yet fully known. Usually, these toxins are purified directly from the natural source, extracted venom, and purity is a challenge due to the co-existence of various isoforms. Thus, crystals may contain heterogeneous species not fully characterized. We will address this question by proposing an algorithm, called SEQUENCE SLIDER (SLIDER), to evaluate different sequence possibilities against crystallographic data. We will train our algorithm through the analysis of the data of PLA2-like toxins already available in the protein databank and apply SLIDER to unknown crystallographic structures. Furthermore, sequence uncertainty scenario is immediately applicable to phasing program ARCIMBOLDO when dealing with datasets of lower resolution than its usual scope of 2.0 Å. We will develop SLIDER also to enhance partial models in ARCIMBOLDO, usually composed of polyalanine, by incorporation of side chains and extend this phasing method to lower resolutions. On the other side, evaluating the PLA2s-like structures, we will relate oligomeric flexibility to their mechanism of action, since dimeric assembly and exposed residues are essential to myotoxicity. We will also analyze this flexibility through Low Frequency Normal Mode, as these may describe real protein movements related to fundamental biological properties. For this purpose, we will establish relationship between exposition of these important residues, natural movement between monomers and membrane disruption. Thus, the objectives of this project are to develop and implement new algorithm that aids toxin structure elucidation and to related PLA2-like mechanism of action to structural flexibility. | |
| News published in Agência FAPESP Newsletter about the scholarship: | |
| More itemsLess items | |
| TITULO | |
| Articles published in other media outlets ( ): | |
| More itemsLess items | |
| VEICULO: TITULO (DATA) | |
| VEICULO: TITULO (DATA) | |