Please use this identifier to cite or link to this item:
Type: Artigo de periódico
Title: Flavonoid interactions with human transthyretin: Combined structural and thermodynamic analysis
Author: Trivella, Daniela B. B.
dos Reis, Caio V.
Lima, Luis Mauricio T. R.
Foguel, Debora
Polikarpov, Igor
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.
Subject: Crystal structure
Isothermal titration calorimetry
Wild type TTR
TTR V30M mutant
TTR amyloid inhibitor
Editor: Elsevier
Citation: Journal of Structural Biology. Elsevier, v.180, n.1, p.143-153, 2012
Rights: fechado
Identifier DOI: 10.1016/j.jsb.2012.07.008
Date Issue: 2012
Appears in Collections:IQ - Artigos e Outros Documentos

Files in This Item:
There are no files associated with this item.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.