8W47

X-ray crystal structure of V30M-TTR in complex with isorhapontigenin

8W47 の概要

• エントリーDOI: 10.2210/pdb8w47/pdb
• 分子名称: Transthyretin, 5-[(~{E})-2-(3-methoxy-4-oxidanyl-phenyl)ethenyl]benzene-1,3-diol, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: amyloidogenesis, inhibitor, resveratrol, thyroid hormone, 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: 35247.68

構造登録者

Yokoyama, T. (登録日: 2023-08-23, 公開日: 2023-11-22, 最終更新日: 2023-12-06)

主引用文献

Yokoyama, T.,Kusaka, K.,Mizuguchi, M.,Nabeshima, Y.,Fujiwara, S.
Resveratrol Derivatives Inhibit Transthyretin Fibrillization: Structural Insights into the Interactions between Resveratrol Derivatives and Transthyretin.
J.Med.Chem., 66:15511-15523, 2023

PubMed Abstract: Hereditary ATTR amyloidosis is a disease caused by the deposition of amyloid fibrils formed by mutated transthyretin (TTR), a protein that binds to thyroid hormone in the serum, in the organs. The development of a small molecule that binds to and stabilizes TTR is a promising strategy for the treatment of ATTR amyloidosis. In the present study, we demonstrated that the resveratrol derivatives including pterostilbene available as a dietary supplement inhibit the fibrillization of V30M-TTR to the same extent as the approved drug tafamidis. Furthermore, based on a thermodynamic and X-ray crystallographic analysis, the binding of the resveratrol derivative to TTR was shown to be enthalpy-driven, with the binding enthalpy being acquired by hydrogen bonding to S117. Moreover, direct observation of hydrogen atoms by neutron crystallography provided details of the hydrogen bond network by S117 and emphasized the importance of the CH···π interaction by L110 in the ligand binding.

PubMed: 37910439
DOI: 10.1021/acs.jmedchem.3c01698

実験手法

X-RAY DIFFRACTION (1.4 Å)