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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.)

Dynamics of Nuclear Receptor Helix-12 Switch of Transcription Activation by Modeling Time-Resolved Fluorescence Anisotropy Decays

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Author(s):
Batista, Mariana R. B. [1] ; Martinez, Leandro [2]
Total Authors: 2
Affiliation:
[1] Univ Sao Paulo, Inst Phys Sao Carlos, Sao Carlos, SP - Brazil
[2] Univ Estadual Campinas, Inst Chem, Campinas, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: BIOPHYSICAL JOURNAL; v. 105, n. 7, p. 1670-1680, OCT 1 2013.
Web of Science Citations: 23
Abstract

Nuclear hormone receptors (NRs) are major targets for pharmaceutical development. Many experiments demonstrate that their C-terminal Helix (H12) is more flexible in the ligand-binding domains (LBDs) without ligand, this increased mobility being correlated with transcription repression and human diseases. Crystal structures have been obtained in which the H12 is extended, suggesting the possibility of large amplitude H12 motions in solution: However, these structures were interpreted as possible crystallographic artifacts, and thus the microscopic nature of H12 movements is not well known. To bridge the gap between experiments and molecular models and provide a definitive picture of H12 motions in solution, extensive molecular dynamics simulations of the peroxisome proliferator-activated receptor-gamma LBD, in which the H12 was bound to a fluorescent probe, were performed. A direct comparison of the modeled anisotropy decays to time-resolved fluorescence anisotropy experiments was obtained. It is shown that the decay rates are dependent on the interactions of the probe with the surface of the protein, and display little correlation with the flexibility of the H12. Nevertheless, for the probe to interact with the surface of the LBD, the H12 must be folded over the body of the LBD. Therefore, the molecular mobility of the H12 should preserve the globularity of the LBD, so that ligand binding and dissociation occur by diffusion through the surface of a compact receptor. These results advance the comprehension of both ligand-bound and ligand-free receptor structures in solution, and also guide the interpretation of time-resolved anisotropy decays from a molecular perspective, particularly by the use of simulations. (AU)

FAPESP's process: 10/16947-9 - Correlations between dynamics, structure and function in protein: computer simulations and algorithms
Grantee:Leandro Martinez
Support type: Regular Research Grants