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| Author(s): |
Paulo Cesar Telles de Souza
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Instituto de Química |
| Defense date: | 2009-07-30 |
| Examining board members: |
Munir Salomão Skaf;
Pedro Geraldo Pascutti;
Watson Loh
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| Advisor: | Munir Salomão Skaf |
| Abstract | |
Nuclear Receptors (NRs) are proteins that have role of regulating the transcription of genes through the association with hormones. The NRs are formed by up to four domains, being the Ligant Binding Domain (LBD) the most important one. Thyroid hormone receptor (TR) is responsible for several functions in the body, such as control of the heart rate and of the metabolism of lipids. There are two groups of the TR isoforms: a and b. Differences between them are important for the design of new selective drugs to be used in the treatment of thyroid disorders such as resistance to thyroid hormone syndrome (RTH), caused by mutations in TRb. There are just a few studies that show how structural and dynamical changes caused by mutations may lead to functional loss. In this work we studied the effects of mutations in the structure of the TRb LBD by applying molecular dynamics technique. First, we have chosen five mutants for a more detailed investigation. We found that two of three studied mutations in residue I280 caused structural changes in helix H12, what can explain the loss of interaction with coregulators, recently seen in experiments. We also found that these and other changes induce the water entrance in the binding site. On the other hand, the L428R and R429Q mutants have shown important differences related to native structure in the dimerization region, helix H12 (which interacts with coregulators) and b-hairpin (involved in the dissociation of hormones). The results of global analysis carried out for 40 mutants showed that the mutations are greatly responsible for instability of LDB region, loss of interaction with hormone and water entrance even in hydrophobic regions. These results may explain the loss of affinity with the hormone, even when the mutated region is located far from the ligand binding site (AU) | |
| FAPESP's process: | 07/02017-7 - Molecular dynamics simulations of nuclear thyroid hormone receptor mutants |
| Grantee: | Paulo Cesar Telles de Souza |
| Support Opportunities: | Scholarships in Brazil - Master |