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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Low-Resolution Molecular Models Reveal the Oligomeric State of the PPAR and the Conformational Organization of Its Domains in Solution

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Bernardes, Amanda [1] ; Batista, Fernanda A. H. [1] ; Neto, Mario de Oliveira [1] ; Figueira, Ana Carolina M. [2] ; Webb, Paul [3, 4] ; Saidemberg, Daniel [5, 6] ; Palma, Mario S. [5, 6] ; Polikarpov, Igor [1]
Total Authors: 8
[1] Univ Sao Paulo, Inst Phys Sao Carlos, Sao Paulo - Brazil
[2] CNPEM, Natl Lab Biosci, Sao Paulo - Brazil
[3] Methodist Hosp, Ctr Diabet, Houston, TX 77030 - USA
[4] Methodist Hosp, Canc Res Unit, Houston, TX 77030 - USA
[5] Univ Estadual Sao Paulo UNESP, Inst Biosci Rio Claro, Dept Biol, Ctr Study Social Insects CEIS, Sao Paulo - Brazil
[6] Natl Inst Sci & Technol Immunol INCT Iii, Sao Paulo - Brazil
Total Affiliations: 6
Document type: Journal article
Source: PLoS One; v. 7, n. 2 FEB 21 2012.
Web of Science Citations: 12

The peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid and carbohydrate metabolism, and are targets of drugs approved for human use. Whereas the crystallographic structure of the complex of full length PPAR gamma and RXR alpha is known, structural alterations induced by heterodimer formation and DNA contacts are not well understood. Herein, we report a small-angle X-ray scattering analysis of the oligomeric state of hPPAR gamma alone and in the presence of retinoid X receptor (RXR). The results reveal that, in contrast with other studied nuclear receptors, which predominantly form dimers in solution, hPPAR gamma remains in the monomeric form by itself but forms heterodimers with hRXR alpha. The low-resolution models of hPPAR gamma/RXR alpha complexes predict significant changes in opening angle between heterodimerization partners (LBD) and extended and asymmetric shape of the dimer (LBD-DBD) as compared with X-ray structure of the full-length receptor bound to DNA. These differences between our SAXS models and the high-resolution crystallographic structure might suggest that there are different conformations of functional heterodimer complex in solution. Accordingly, hydrogen/deuterium exchange experiments reveal that the heterodimer binding to DNA promotes more compact and less solvent-accessible conformation of the receptor complex. (AU)

FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
Grantee:Igor Polikarpov
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 10/17048-8 - Regulation of genic transactivation and transrepression mediated by nuclear receptors
Grantee:Ana Carolina Migliorini Figueira
Support Opportunities: Regular Research Grants
FAPESP's process: 08/00078-1 - Structure and biophysical studies of complexes of nuclear receptors, ligands, DNA responsive elements and corregulators proteins
Grantee:Ana Carolina Migliorini Figueira
Support Opportunities: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 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
Grantee:Mario de Oliveira Neto
Support Opportunities: Scholarships in Brazil - Post-Doctorate