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metadata.dc.type: bachelorThesis
Título : Structural Analysis of Protein Tyrosine Phosphatases
Otros títulos : Análisis estructural de las tirosina fosfatasas como blancos moleculares específicos en el desarrollo de fármacos
Autor : Rodríguez Cabezas, Johanna Gabriela
metadata.dc.contributor.advisor: Tabernero, Lydia
Fecha de publicación : 25-abr-2016
Editorial : Mánchester / Universidad de Mánchester
Citación : Rodríguez Cabezas, Johanna Gabriela. (2016). Structural Analysis of Protein Tyrosine Phosphatases. (Trabajo de titulación de Licencitura con HOnores en Ciencias de Farmacología y Fisiología). Universidad de Mánchester. Mánchester. 34 p.
Resumen : Protein Tyrosine Phosphatases have a major role in cellular pathways including cell homeostasis. Their main structural features are the WPD-loop, and the P-loop (catalytic active site) with its conserved cysteine and arginine residues. This study focus in three PTP families: 1) the PRLs which are involved in cell proliferation and their overexpression is linked to cancer; 2) the PTENs which have a lipid phosphatase activity, and have a tumour suppressor activity; 3) the MTMs which have a lipid phosphatase activity, and their functions are related with cellular transport and autophagy. The high homology among the PTP catalytic active site impedes the development of selective inhibitors with good cell bioavailability and high potency. The main objective of this structural analysis study in PRLs, PTENs, and MTMs is to identify unique binding pockets through the investigation of possible proteinprotein interactions (MetaPPI) or binding pockets (MetaPocket and VINA blind docking). For the first part of the study, three different approaches (VINA blind docking, MetaPPI, and MetaPocket) were used to compare one representative member of the PRLs (PT4A1 – PDB ID: 1X24), the PTENs (PTEN – PDB ID: 1D5R), and the MTMs (MTMR8 – PDB ID: 4Y7I). For the second part of the study, analysis of the binding pockets within the PTENs (PTEN – PDB ID: 1D5R; TNS3 – PDB ID: 5BUD; TPTE and TPTE2 – 54% homology model of 3VOF) and MTMs (MTMR7 – 66% homology model of 4Y7I; MTMR8 – PDB ID: 4Y7I; MTMR9 – 39% homology of 4Y7I) were done through VINA blind docking. The conservation of each pocket across each family was analysed through a multiple sequence alignment study done in Clustal omega. The results showed that the binding pockets found through VINA blind docking was in agreement with MetaPocket, and that some of the PPI found through MetaPPI were not present in the other two approaches. The most common binding pockets found were close to the active site and to the WPD-loop, except for PRLs that none of the binding pockets were present in the active site because of the presence of a sulphide bond. PRLs showed six binding pockets, and one of them was unique. This pocket was near to the C-terminal and α3, which is involved in the formation of trimers in PRLs. Trimerization is usually seen in cancer, so this makes this pocket a possible target for selective inhibitor development. PTENs presented six pockets, and two of them were unique. The first pocket was located close to TI-loop and α4 and α5, and the second pocket was in the C2-terminal domain. The C2-terminal domain controls substrate binding to the active site and phosphorylation of PI, so it linked directly to the active site which could be an advantage to create an allosteric drug. MetaPPI showed a non-conserved region (SEDDNH) across the PTEN family localised in α2, but little is known about α2 in the literature. TNS3, TPTE, and TPTE2 showed the same distribution of pockets than PTEN. MTMs had four pockets, and two of them were unique for this family. The first one was located close to α16, α8, and α7, and the second was in the SID domain. All this pockets were conserved in MTMR7, MTMR8, and MTMR9, except for MTMR9 which presented two new pockets close to the RID domain suggesting possible selectivity. In comparison with blind docking studies done in DUSPs and Classic receptor and non receptor, the previously mentioned binding pockets were unique for each family suggesting that these pockets may be good targets for selectivity. However, more investigation regarding the validity of these pockets using other library with commercially available compounds will be necessary.
URI : http://repositorio.educacionsuperior.gob.ec/handle/28000/4196
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