6TJN

Human transthyretin (TTR) complexed with (E)-3-(((4-hydroxybenzylidene)amino)oxy)propanoic acid

Summary for 6TJN

• Entry DOI: 10.2210/pdb6tjn/pdb
• Descriptor: Transthyretin, 3-[(~{E})-(4-hydroxyphenyl)methylideneamino]oxypropanoic acid (3 entities in total)
• Functional Keywords: transthyretin, ttr, inhibitor, complex, protein transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28087.22

Authors

Ciccone, L.,Shepard, W.,Nencetti, S.,Orlandini, E.,Rossello, A. (deposition date: 2019-11-26, release date: 2020-12-16, Last modification date: 2024-01-24)

Primary citation

Ciccone, L.,Nencetti, S.,Tonali, N.,Fruchart-Gaillard, C.,Shepard, W.,Nuti, E.,Camodeca, C.,Rossello, A.,Orlandini, E.
Monoaryl derivatives as transthyretin fibril formation inhibitors: Design, synthesis, biological evaluation and structural analysis.
Bioorg.Med.Chem., 28:115673-115673, 2020

PubMed Abstract: Transthyretin (TTR) is a ß-sheet-rich homotetrameric protein that transports thyroxine (T4) and retinol both in plasma and in cerebrospinal fluid. TTR also interacts with amyloid-β, playing a protective role in Alzheimer's disease. Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloids fibrillogenesis, and is responsible for extracellular deposition of amyloid fibrils. Small molecules, able to bind in T4 binding sites and stabilize the TTR tetramer, are interesting tools to treat and prevent systemic ATTR amyloidosis. We report here the synthesis, in vitro evaluation and three-dimensional crystallographic analyses of new monoaryl-derivatives in complex with TTR. Of the derivatives reported here, the best inhibitor of TTR fibrillogenesis, 1d, exhibits an activity similar to diflunisal.

PubMed: 32828431
DOI: 10.1016/j.bmc.2020.115673

Experimental method

X-RAY DIFFRACTION (1.702 Å)