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Structural biophysics of nuclear receptors and related proteins

Grant number: 06/00182-8
Support type:Research Projects - Thematic Grants
Duration: June 01, 2006 - October 31, 2009
Field of knowledge:Biological Sciences - Biophysics
Cooperation agreement: NSF - American Universities (Chemistry)
Principal Investigator:Igor Polikarpov
Grantee:Igor Polikarpov
Principal investigator abroad: Adrian E. Roitberg
Institution abroad: University of Florida, Gainesville (UF), United States
Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Co-Principal Investigators:Munir Salomao Skaf
Associated scholarship(s):10/08585-0 - Molecular dynamics simulations of systems involving the peroxissome proliferator activated receptor, BP.DR
09/14333-6 - Structural characterization of the peroxisome proliferator-activated receptors (PPARs) types alpha and gamma complexes and its agonists, BP.DD
09/14108-2 - Molecular dynamics simulations of nuclear receptors: ligand-protein free energy estimates, BP.DR
+ associated scholarships 09/10901-0 - Search for new agonists of the PPARy, BP.IC
09/05328-9 - Expression, purification and cristalization studies of the ligand-binding domain of nuclear receptors PPAR-alpha e PPAR-gamma, BP.IC
08/08718-0 - Expression, purification, biochemistry analysis and crystalization essays of the coactivator GRIP-1, beyond studies of its interaction with the thyroidian receptor (tr), BP.IC
08/05637-9 - Structural studies of the three isotypes of the peroxisomal proliferator-activated receptor hPPAR and them interaction with retinoid receptor hRXRalfa using small angle X-ray scattering, BP.PD
08/01236-0 - Molecular dynamics of androgen nuclear receptors: native structure and functionally important mutants, BP.PD
08/00078-1 - Structure and biophysical studies of complexes of nuclear receptors, ligands, DNA responsive elements and corregulators proteins, BP.PD - associated scholarships

Abstract

Nuclear receptors are among the most important intracellular regulating molecules, that convey diverse internal and external signals into regulation of genetic programs. Genetic programming established or modified by these proteins affect virtually all the aspects of life of multicellular organisms. Transcriptional regulation and selectivity promoted by nuclear receptors nourished their intensive research in attempts to decipher complex network of molecular events that promoted by their capacity of transcriptional regulation and to discover molecular rules which define their control, in space and time, over protein-protein and protein-DNA interactions, opening possibilities for developing of more efficient drugs with superior therapeutical values. Within the present project, we plan to study nuclear receptors by X-ray crystallography, small angle X-ray scattering (SAXS), biochemical and biophysical methods as well as by biocomputing simulations, in attempt to decipher what conformational changes of the receptor 3D structures are induced by its binding to specific ligands (agonists and antagonist) and how this influence receptors oligomeric state state and its interactions with coregulating proteins (coactivators and corepressors), and also modify their stability. We aim to gain insights into recognition of the nuclear receptors DNA response elements by a combined approach of protein crystallography, SAXS and fluorescence anisotropy. Finally, we plan to study the role of nuclear receptors dynamics and flexibility in their function, aiming to determine the preferable dissociation pathways of the nuclear receptor ligands from their respective receptors by molecular dynamics simulations and experimental studies of the mobility and solvent accessibility changes using hydrogen/deuterium exchange combined with mass-spectroscopy. It is important to stress that these aims have an immediate impact on rational development of hormone agonists and antagonists; insert themselves within perspectives of scientific and technical development of Brazil in the area of nuclear receptors and are directly related to the interests of pharmaceutical industry, medicine and productive sector. (AU)

Scientific publications (24)
(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)
PUHL, ANA C.; WEBB, PAUL; POLIKARPOV, IGOR. Structural dataset for the PPAR gamma V290M mutant. DATA IN BRIEF, v. 7, p. 1430-1437, JUN 2016. Web of Science Citations: 1.
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; AMATO, ANGELA ANGELICA; TOGASHI, MARIE; HSUEH, WILLA A.; PHILLIPS, KEVIN; PALMA, MARIO SERGIO; NEVES, FRANCISCO A. R.; SKAF, MUNIR S.; WEBB, PAUL; POLIKARPOV, IGOR. Medium Chain Fatty Acids Are Selective Peroxisome Proliferator Activated Receptor (PPAR) gamma Activators and Pan-PPAR Partial Agonists. PLoS One, v. 7, n. 5 MAY 23 2012. Web of Science Citations: 70.
BATISTA, FERNANDA A. H.; TRIVELLA, DANIELA B. B.; BERNARDES, AMANDA; GRATIERI, JOYCE; OLIVEIRA, PAULO S. L.; FIGUEIRA, ANA CAROLINA M.; WEBB, PAUL; POLIKARPOV, IGOR. Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding. PLoS One, v. 7, n. 5 MAY 11 2012. Web of Science Citations: 25.
BERNARDES, AMANDA; BATISTA, FERNANDA A. H.; NETO, MARIO DE OLIVEIRA; FIGUEIRA, ANA CAROLINA M.; WEBB, PAUL; SAIDEMBERG, DANIEL; PALMA, MARIO S.; POLIKARPOV, IGOR. Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution. PLoS One, v. 7, n. 2 FEB 21 2012. Web of Science Citations: 12.
FIGUEIRA, A. C. M.; SAIDEMBERG, D. M.; SOUZA, P. C. T.; MARTINEZ, L.; SCANLAN, T. S.; BAXTER, J. D.; SKAF, M. S.; PALMA, M. S.; WEBB, P.; POLIKARPOV, I. Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange. MOLECULAR ENDOCRINOLOGY, v. 25, n. 1, p. 15-31, JAN 2011. Web of Science Citations: 31.
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, OCT 2010. Web of Science Citations: 12.
WATANABE, LEANDRA; DE MOURA, PATRICIA RIBEIRO; BLEICHER, LUCAS; NASCIMENTO, ALESSANDRO S.; ZAMORANO, LAURA S.; CALVETE, JUAN J.; SANZ, LIBIA; PEREZ, ALICIA; BURSAKOV, SERGEY; ROIG, MANUEL G.; SHNYROV, VALERY L.; POLIKARPOV, IGOR. Crystal structure and statistical coupling analysis of highly glycosylated peroxidase from royal palm tree (Roystonea regia). Journal of Structural Biology, v. 169, n. 2, p. 226-242, Feb. 2010. Web of Science Citations: 31.
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, JAN 28 2010. Web of Science Citations: 5.
MIGLIORINI FIGUEIRA, ANA CAROLINA; LIMA, LUIS MAURICIO T. R.; LIMA, LEONARDO H. F.; RANZANI, AMERICO T.; MULE, GUILHERME DOS SANTOS; POLIKARPOV, IGOR. Recognition by the Thyroid Hormone Receptor of Canonical DNA Response Elements. BIOCHEMISTRY, v. 49, n. 5, p. 893-904, 2010. Web of Science Citations: 10.
MARTINEZ, LEANDRO; NASCIMENTO, ALESSANDRO S.; NUNES, FABIO M.; PHILLIPS, KEVIN; APARICIO, RICARDO; DIAS, SANDRA MARTHA G.; FIGUEIRA, ANA CAROLINA M.; LIN, JEAN H.; NGUYEN, PHUONG; APRILETTI, JAMES W.; NEVES, FRANCISCO A. R.; BAXTER, JOHN D.; WEBB, PAUL; SKAF, MUNIR S.; POLIKARPOV, IGOR. Gaining ligand selectivity in thyroid hormone receptors via entropy. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 106, n. 49, p. 20717-20722, DEC 8 2009. Web of Science Citations: 50.
CUNHA LIMA, SUZANA T.; NGUYEN, NGOC-HA; TOGASHI, MARIE; APRILETTI, JAMES W.; NGUYEN, PHUONG; POLIKARPOV, IGOR; SCANLAN, THOMAS S.; BAXTER, JOHN D.; WEBB, PAUL. Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways. JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, v. 117, n. 4-5, p. 125-131, NOV 2009. Web of Science Citations: 3.
DE MOURA, PATRICIA RIBEIRO; WATANABE, LEANDRA; BLEICHER, LUCAS; COLAU, DIDIER; DUMOUTIER, LAURE; LEMAIRE, MURIEL M.; RENAULD, JEAN-CHRISTOPHE; POLIKARPOV, IGOR. Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22. FEBS Letters, v. 583, n. 7, p. 1072-1077, APR 2 2009. Web of Science Citations: 30.
WATANABE, LEANDRA; DE MOURA, PATRICIA RIBEIRO; NASCIMENTO, ALESSANDRO SILVA; COLAU, DIDIER; DUMOUTIER, LAURE; RENAULD, JEAN-CHRISTOPHE; POLIKARPOV, IGOR. Crystallization and preliminary X-ray diffraction analysis of human IL-22 bound to its soluble decoy receptor IL-22BP. ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS, v. 65, n. 2, p. 102-104, FEB 2009. Web of Science Citations: 1.
KRAUCHENCO, SANDRA; MARTINS, NADIA H.; SANCHES, MARIO; POLIKARPOV, IGOR. Effectiveness of commercial inhibitors against subtype F HIV-1 protease. Journal of Enzyme Inhibition and Medicinal Chemistry, v. 24, n. 3, p. 638-645, 2009. Web of Science Citations: 4.
GARCIA, WANIUS; FIGUEIRA, ANA CAROLINA M.; NETO, MARIO DE OLIVEIRA; DE GUZZI, CAROLINA A.; BUZZA, HILDE H.; PORTUGAL, RODRIGO V.; CALGARO, MARCOS R.; POLIKARPOV, IGOR. Probing conformational changes in orphan nuclear receptor: The NGFI-B intermediate is a partially unfolded dimer. Biophysical Chemistry, v. 137, n. 2-3, p. 81-87, OCT 2008. Web of Science Citations: 1.
GOLUBEV, ALEXANDER M.; ROJAS, ADRIANA L.; NASCIMENTO, ALESSANDRO S.; BLEICHER, LUCAS; KULMINSKAYA, ANNA A.; ENEYSKAYA, ELENA V.; POLIKARPOV, IGOR. Crystallization and Preliminary Crystallographic Analysis of Laminarinase from Rhodothermus marinus: A Case of Pseudomerohedral Twinning. PROTEIN AND PEPTIDE LETTERS, v. 15, n. 10, p. 1142-1144, OCT 2008. Web of Science Citations: 1.
BLEICHER, LUCAS; DE MOURA, PATRICIA RIBEIRO; WATANABE, LEANDRA; COLAU, DIDIER; DUMOUTIER, LAURE; RENAULD, JEAN-CHRISTOPHE; POLIKARPOV, IGOR. Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Letters, v. 582, n. 20, p. 2985-2992, SEP 3 2008. Web of Science Citations: 58.
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, AUG 28 2008. Web of Science Citations: 49.
KIM, KYOUNG-YUN; NASCIMENTO, ALESSANDRO S.; GOLUBEV, ALEXANDER M.; POLIKARPOV, IGOR; KIM, CHUNG-SEI; KANG, SU-IL; KIM, SU-IL. Catalytic mechanism of inulinase from Arthrobacter sp. S37. Biochemical and Biophysical Research Communications, v. 371, n. 4, p. 600-605, July 2008.
BLEICHER‚ L.; APARICIO‚ R.; NUNES‚ F.; MARTINEZ‚ L.; DIAS‚ S.G.; FIGUEIRA‚ A.; SANTOS‚ M.; VENTURELLI‚ W.; DA SILVA‚ R.; DONATE‚ P.; OTHERS. Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms. BMC STRUCTURAL BIOLOGY, v. 8, n. 1, p. 8, 2008.
AMBROSIO, ANDRE L. B.; DIAS, SANDRA M. G.; POLIKARPOV, IGOR; ZURIER, ROBERT B.; BURSTEIN, SUMNER H.; GARRATT, RICHARD C. Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma. Journal of Biological Chemistry, v. 282, n. 25, p. 18625-18633, June 2007.
MATOZO‚ H.C.; SANTOS‚ M.A.M.; DE OLIVEIRA NETO‚ M.; BLEICHER‚ L.; LIMA‚ L.M.T.R.; IULIANO‚ R.; FUSCO‚ A.; POLIKARPOV‚ I. Low-Resolution Structure and Fluorescence Anisotropy Analysis of Protein Tyrosine Phosphatase [eta] Catalytic Domain. BIOPHYSICAL JOURNAL, v. 92, n. 12, p. 4424-4432, 2007.
NASCIMENTO‚ A.; CATALANO-DUPUY‚ D.; BERNARDES‚ A.; NETO‚ M.; SANTOS‚ M.; CECCARELLI‚ E.; POLIKARPOV‚ I. Crystal structures of Leptospira interrogans FAD-containing ferredoxin-NADP+ reductase and its complex with NADP+. BMC STRUCTURAL BIOLOGY, v. 7, n. 1, p. 69, 2007.
NASCIMENTO, ALESSANDRO S.; DIAS, SANDRA MARTHA GOMES; NUNES, FÁBIO M.; APARÍCIO, RICARDO; AMBROSIO, ANDRE L. B.; BLEICHER, LUCAS; FIGUEIRA, ANA CAROLINA M.; SANTOS, MARIA AUXILIADORA M.; OLIVEIRA NETO, MÁRIO DE; FISCHER, HANNES; ET AL. Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function. Journal of Molecular Biology, v. 360, n. 3, p. 586-598, July 2006.

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