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Molecular dynamics simulations of thyroid hormone receptors

Grant number: 06/06831-8
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): April 01, 2007
Effective date (End): June 30, 2010
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Munir Salomao Skaf
Grantee:Leandro Martinez
Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Nuclear hormone receptors form an important family of trascription factors. They are DNA-binding proteins, and are regulated by the binding of hormones (Estrogen, Thyroid Hormone, Retinoic Acid, among others). The specific binding to DNA and regulated hormone binding determine whether a gene will be transcripted or repressed. Since 1995 several three-dimensional structures of the LBD of nuclear receptors were obtained, allowing for important advances in the comprehension of the molecular biology of hormone recognition. However, in spite of the fact that new structures were obtained for different receptors, the role of the dynamics of the receptors remained fundamentally unknown. As a graduate student, I studied everal aspects of the dynamics of nuclear hormone receptors and their role in the biological function of these proteins. We obtained results that associate the dynamics of the receptors to their function in various different areas, such as hormone binding and dissociation, ligand selectivity and denaturation mechanisms, for example. The use of new techniques for expanding these results may complement our studies in a important way, leading to one of the most comprehensive set of data on the dynamics of nuclear hormone receptors. Three main new areas of research are proposed in this project:1. The study of ligand entry into the receptors. 2. The identification of transition states of protein denaturation. 3. To obtain optimal dissociation paths.

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Scientific publications (4)
(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)
LIBERATO, MARCELO VIZONA; NASCIMENTO, ALESSANDRO S.; AYERS, STEVEN D.; LIN, JEAN Z.; CVORO, ALEKSANDRA; SILVEIRA, RODRIGO L.; MARTINEZ, LEANDRO; SOUZA, PAULO C. T.; SAIDEMBERG, DANIEL; DENG, TUO; et al. Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) gamma Activators and Pan-PPAR Partial Agonists. PLoS One, v. 7, n. 5, . (06/06831-8, 06/00182-8)
MARTINEZ, LEANDRO; POLIKARPOV, IGOR; SKAF, MUNIR S.. Only subtle protein conformational adaptations are required for ligand binding to thyroid hormone receptors: Simulations using a novel multipoint steered molecular dynamics approach. Journal of Physical Chemistry B, v. 112, n. 34, p. 10741-10751, . (06/06831-8, 06/00182-8)
MARTINEZ, LEANDRO; SOUZA, PAULO C. T.; GARCIA, WANIUS; BATISTA, FERNANDA A. H.; PORTUGAL, RODRIGO V.; NASCIMENTO, ALESSANDRO S.; NAKAHIRA, MARCEL; LIMA, LUIS M. T. R.; POLIKARPOV, IGOR; SKAF, MUNIR S.. On the Denaturation Mechanisms of the Ligand Binding Domain of Thyroid Hormone Receptors. Journal of Physical Chemistry B, v. 114, n. 3, p. 1529-1540, . (06/06831-8, 06/00182-8)
DE ARAUJO, ALEXANDRE SUMAN; MARTINEZ, LEANDRO; NICOLUCI, RICARDO DE PAULA; SKAF, MUNIR S.; POLIKARPOV, IGOR. Structural modeling of high-affinity thyroid receptor-ligand complexes. EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, v. 39, n. 11, p. 1523-1536, . (06/06831-8, 06/01977-4, 06/00182-8)

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