8W47

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

Summary for 8W47

• Entry DOI: 10.2210/pdb8w47/pdb
• Descriptor: Transthyretin, 5-[(~{E})-2-(3-methoxy-4-oxidanyl-phenyl)ethenyl]benzene-1,3-diol, SODIUM ION, ... (4 entities in total)
• Functional Keywords: amyloidogenesis, inhibitor, resveratrol, thyroid hormone, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 35247.68

Authors

Yokoyama, T. (deposition date: 2023-08-23, release date: 2023-11-22, Last modification date: 2023-12-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.4 Å)