| Full text | |
| Author(s): |
de Oliveira, Vinicius M.
;
Malospirito, Caique C.
;
da Silva, Fernando B.
;
Videira, Natalia B.
;
Dias, Marieli M. G.
;
Sanches, Murilo N.
;
Leite, Vitor B. P.
;
Figueira, Ana Carolina M.
Total Authors: 8
|
| Document type: | Journal article |
| Source: | Journal of Chemical Physics; v. 161, n. 16, p. 10-pg., 2024-10-28. |
| Abstract | |
The intricate involvement of Peroxisome Proliferator-Activated Receptor Gamma (PPAR gamma) in glucose homeostasis and adipogenesis is well-established. However, its role in cancer, particularly luminal bladder cancer, remains debated. The overexpression and activation of PPAR gamma are implicated in tumorigenesis. Specific gain-of-function mutations (M280I, I290M, and T475M) within the ligand-binding domain of PPAR gamma are associated with bladder cancer and receptor activation. The underlying molecular pathways prompted by these mutations remain unclear. We employed a dual-basin structure-based model (db-SBM) to explore the conformational dynamics between the inactive and active states of PPAR gamma and examined the effects of the M280I, I290M, and T475M mutations. Our findings, consistent with the existing literature, reveal heightened ligand-independent transcriptional activity in the I290M and T475M mutants. Both mutants showed enhanced stabilization of the active state compared to the wild-type receptor, with the I290M mutation promoting a specific transition route, making it a prime candidate for further study. Electrostatic analysis identified residues K303 and E488 as pivotal in the I290M activation cascade. Biophysical assays confirmed that disrupting the K303-E488 interaction reduced the thermal stabilization characteristic of the I290M mutation. Our study demonstrates the predictive capabilities of combining simulation and cheminformatics methods, validated by biochemical experiments, to gain insights into molecular activation mechanisms and identify target residues for protein modulation. (AU) | |
| FAPESP's process: | 23/02219-1 - Understanding functional mechanisms of proteins and RNAs through energy landscapes |
| Grantee: | Vitor Barbanti Pereira Leite |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 19/14465-1 - Dissection of PPAR gama modulation mechanisms as target to treat diabetes and obesity development |
| Grantee: | Ana Carolina Migliorini Figueira |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 16/02348-2 - STRUCTURAL STUDIES OF THE INTERACTION OF NORMAL AND PATHOLOGICAL RAR AND THR WITH COREPRESSORS. |
| Grantee: | Tábata Renée Doratioto |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 18/11614-3 - Effect of pH and Cancer-Activating Mutations on Functional Transition of Estrogen Receptor |
| Grantee: | Vinicius Martins de Oliveira |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 20/08366-8 - Characterization of the interaction of nuclear receptor PPAR³ with the deacetylase SIRT1 under influence of its phosphorylation in the context of metabolic homeostasis regulation |
| Grantee: | Caique Camargo Malospirito |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 21/15028-4 - Elucidating the functional plasticity of intrinsically disordered proteins by the study of energy landscape |
| Grantee: | Murilo Nogueira Sanches |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 19/22540-3 - Studies of energy landscapes of biological macromolecules |
| Grantee: | Vitor Barbanti Pereira Leite |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 19/10274-7 - Study of the PPARy-coregulators interactions and its relationship with adipogenesis and insulin resistance |
| Grantee: | Marieli Mariano Gonçalves Dias |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 22/07231-7 - Plasticity and functional modulation of intrinsically disordered proteins |
| Grantee: | Vitor Barbanti Pereira Leite |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 16/19766-1 - Biological macromolecules energy landscapes with applications in biotechnology and in biomedicine |
| Grantee: | Vitor Barbanti Pereira Leite |
| Support Opportunities: | Regular Research Grants |