7DT6

Crystal structure of V30M mutated transthyretin in complex with purpurin

Summary for 7DT6

• Entry DOI: 10.2210/pdb7dt6/pdb
• Descriptor: Transthyretin, Purpurin (3 entities in total)
• Functional Keywords: inhibitor, complex, t4-binding, amyloidosis, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 34941.37

Authors

Kitakami, R.,Yokoyama, T.,Mizuguchi, M. (deposition date: 2021-01-04, release date: 2021-10-13, Last modification date: 2023-11-29)

Primary citation

Kitakami, R.,Inui, K.,Nakagawa, Y.,Sawai, Y.,Katayama, W.,Yokoyama, T.,Okada, T.,Kanamitsu, K.,Nakagawa, S.,Toyooka, N.,Mizuguchi, M.
Inhibitory activities of anthraquinone and xanthone derivatives against transthyretin amyloidogenesis.
Bioorg.Med.Chem., 44:116292-116292, 2021

PubMed Abstract: Transthyretin is a tetrameric protein which functions as a transporter of thyroxine and retinol-binding protein. Misfolding and amyloid aggregation of transthyretin are known to cause wild-type and hereditary transthyretin amyloidosis. Stabilization of the transthyretin tetramer by low molecular weight compounds is an efficacious strategy to inhibit the aggregation pathway in the amyloidosis. Here, we investigated the inhibitory activities of anthraquinone and xanthone derivatives against amyloid aggregation, and found that xanthone-2-carboxylic acid with one chlorine or methyl group has strong inhibitory activity comparable with that of diflunisal, which is one of the best known stabilizers of transthyretin. X-ray crystallographic structures of transthyretin in complex with the compounds revealed that the introduction of chlorine, which is buried in a hydrophobic region, is important for the strong inhibitory effect of the stabilizer against amyloidogenesis. An in vitro absorption, distribution, metabolism and elimination (ADME) study and in vivo pharmacokinetic study demonstrated that the compounds have drug-like features, suggesting that they have potential as therapeutic agents to stabilize transthyretin.

PubMed: 34225167
DOI: 10.1016/j.bmc.2021.116292

Experimental method

X-RAY DIFFRACTION (1.3 Å)