7ACU

Crystal structure of human transthyretin in complex with Benzbromarone

7ACU の概要

• エントリーDOI: 10.2210/pdb7acu/pdb
• 分子名称: Transthyretin, [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone (3 entities in total)
• 機能のキーワード: transthyretin, ttr, benzbromarone, complex, transport protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 26060.37

構造登録者

Leite, J.P.,Gales, L. (登録日: 2020-09-11, 公開日: 2020-10-28, 最終更新日: 2024-01-31)

主引用文献

Cotrina, E.Y.,Oliveira, A.,Leite, J.P.,Llop, J.,Gales, L.,Quintana, J.,Cardoso, I.,Arsequell, G.
Repurposing Benzbromarone for Familial Amyloid Polyneuropathy: A New Transthyretin Tetramer Stabilizer.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: Transthyretin (TTR) is a homotetrameric protein involved in human amyloidosis, including familial amyloid polyneuropathy (FAP). Discovering small-molecule stabilizers of the TTR tetramer is a therapeutic strategy for these diseases. Tafamidis, the only approved drug for FAP treatment, is not effective for all patients. Herein, we discovered that benzbromarone (BBM), a uricosuric drug, is an effective TTR stabilizer and inhibitor against TTR amyloid fibril formation. BBM rendered TTR more resistant to urea denaturation, similarly to iododiflunisal (IDIF), a very potent TTR stabilizer. BBM competes with thyroxine for binding in the TTR central channel, with an IC similar to IDIF and tafamidis. Results obtained by isothermal titration calorimetry (ITC) demonstrated that BBM binds TTR with an affinity similar to IDIF, tolcapone and tafamidis, confirming BBM as a potent binder of TTR. The crystal structure of the BBM-TTR complex shows two molecules binding deeply in the thyroxine binding channel, forming strong intermonomer hydrogen bonds and increasing the stability of the TTR tetramer. Finally, kinetic analysis of the ability of BBM to inhibit TTR fibrillogenesis at acidic pH and comparison with other stabilizers revealed that benzbromarone is a potent inhibitor of TTR amyloidogenesis, adding a new interesting scaffold for drug design of TTR stabilizers.

PubMed: 32998442
DOI: 10.3390/ijms21197166

実験手法

X-RAY DIFFRACTION (1.541 Å)