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Effect of pH and Cancer-Activating Mutations on Functional Transition of Estrogen Receptor

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.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DA SILVA, FERNANDO B.; DE OLIVEIRA, VINICIUS M.; SANCHES, MURILO N.; CONTESSOTO, VINICIUS G.; LEITE, VITOR B. P. Rational Design of Chymotrypsin Inhibitor 2 by Optimizing Non-Native Interactions. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 2, p. 982-988, FEB 2020. Web of Science Citations: 1.
DE OLIVEIRA, VINICIUS M.; CAETANO, DANIEL L. Z.; DA SILVA, FERNANDO B.; MOURO, PAULO R.; DE OLIVEIRA, JR., ANTONIO B.; DE CARVALHO, SIDNEY J.; LEITE, VITOR B. P. pH and Charged Mutations Modulate Cold Shock Protein Folding and Stability: A Constant pH Monte Carlo Study. JOURNAL OF CHEMICAL THEORY AND COMPUTATION, v. 16, n. 1, p. 765-772, JAN 2020. Web of Science Citations: 0.
DA SILVA, FERNANDO BRUNO; CONTESSOTO, VINICIUS G.; DE OLIVEIRA, VINICIUS M.; CLARKE, JANE; LEITE, VITOR B. P. Non-Native Cooperative Interactions Modulate Protein Folding Rates. Journal of Physical Chemistry B, v. 122, n. 48, p. 10817-10824, DEC 6 2018. Web of Science Citations: 3.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.