| Grant number: | 18/11614-3 |
| Support type: | Scholarships in Brazil - Post-Doctorate |
| Effective date (Start): | November 01, 2018 |
| Effective date (End): | October 31, 2021 |
| Field of knowledge: | Biological Sciences - Biochemistry - Chemistry of Macromolecules |
| Principal Investigator: | Ana Carolina Migliorini Figueira |
| Grantee: | Vinicius Martins de Oliveira |
| Home Institution: | Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil |
Abstract Flexibility and conformational changes are fundamental aspects for understanding how proteins perform their biological functions. Experimental and computational works have extensively studied dynamic properties and interactions that lead proteins to different configurations, and how these changes are related to function. One protein that is known to have a disperse set of accessible configurations is the estrogen receptor (ER), which regulates function in several different tissues of both men and women. ER undergoes extensive remodeling as it interacts with different agonists and antagonists, as well as transcription activation and repression factors. Moreover, breast cancer tumors resistant to hormone therapy have been associated with the imbalance between the active and the non-active ER states. The balance between these states is affected by changes in pH and by mutations in ionizable residues. Thus, the main goal of this work is to use simplified models to characterize conformational transitions between the transcriptional active (agonist PDB-1ERE) and non-active (antagonist PDB-1ERR) form of ER.Specifically, the effects of cancer-activating mutations and pH in the ER conformation will be investigated. The computational results will be validated by experiments of affinity between ER and estrogen and cellular activation essay.Finally, the most important residues involved in the ER transition will be identified and, therefore, possible targets for the development of new ER inhibitors will be located. | |