| Full text | |
| Author(s): |
Trivella, Daniela B. B.
[1, 2]
;
dos Reis, Caio V.
[2]
;
Lima, Luis Mauricio T. R.
[3]
;
Foguel, Debora
[4]
;
Polikarpov, Igor
[2]
Total Authors: 5
|
| Affiliation: | [1] Univ Estadual Campinas, Inst Quim, BR-13083970 Campinas, SP - Brazil
[2] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil
[3] Univ Fed Rio de Janeiro, Inst Bioquim Med, BR-21941590 Rio De Janeiro, RJ - Brazil
[4] Univ Fed Rio de Janeiro, Fac Farm, BR-21941590 Rio De Janeiro, RJ - Brazil
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | Journal of Structural Biology; v. 180, n. 1, p. 143-153, OCT 2012. |
| Web of Science Citations: | 24 |
| Abstract | |
Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for ITRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities. (C) 2012 Elsevier Inc. All rights reserved. (AU) | |
| FAPESP's process: | 09/54035-4 - Facility for advanced studies of biosystems and nanostructured materials |
| Grantee: | Igor Polikarpov |
| Support Opportunities: | Multi-user Equipment Program |
| FAPESP's process: | 06/01708-3 - Ligand molecular recognition by human transthyretin (TTR): structural bases for binding to TTR and formation inhibition of amyloid fibers in TTR complexes: ligands |
| Grantee: | Daniela Barretto Barbosa Trivella |
| Support Opportunities: | Scholarships in Brazil - Doctorate |