5U4D

Wild-type Transthyretin in complex with 3-[(1E)-2-(2-Chloro-4-hydroxyphenyl)ethenyl]benzoic Acid

Summary for 5U4D

• Entry DOI: 10.2210/pdb5u4d/pdb
• Related: 5U48 5U49 5U4A 5U4B 5U4C 5U4E 5U4F 5U4G
• Descriptor: Transthyretin, 3-[(E)-2-(2-chloro-4-hydroxyphenyl)ethenyl]benzoic acid (3 entities in total)
• Functional Keywords: boronic acids, medicinal chemistry, stilbene, covalent ligand, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28366.51

Authors

Windsor, I.W.,Smith, T.P.,Raines, R.T.,Forest, K.T. (deposition date: 2016-12-03, release date: 2017-09-27, Last modification date: 2023-10-04)

Primary citation

Smith, T.P.,Windsor, I.W.,Forest, K.T.,Raines, R.T.
Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation.
J. Med. Chem., 60:7820-7834, 2017

PubMed Abstract: Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes. The ensuing structure-function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.

PubMed: 28920684
DOI: 10.1021/acs.jmedchem.7b00952

Experimental method

X-RAY DIFFRACTION (1.55 Å)