7ERH
Crystal structure of WT-TTR in complex with bithionol
Summary for 7ERH
| Entry DOI | 10.2210/pdb7erh/pdb |
| Descriptor | Transthyretin, 2,2'-sulfanediylbis(4,6-dichlorophenol), CALCIUM ION, ... (4 entities in total) |
| Functional Keywords | amyloidosis, inhibitor, complex, transport protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 35057.24 |
| Authors | Yokoyama, T.,Kashihara, M.,Mizuguchi, M. (deposition date: 2021-05-06, release date: 2021-11-24, Last modification date: 2023-11-29) |
| Primary citation | Yokoyama, T.,Kashihara, M.,Mizuguchi, M. Repositioning of the Anthelmintic Drugs Bithionol and Triclabendazole as Transthyretin Amyloidogenesis Inhibitors. J.Med.Chem., 64:14344-14357, 2021 Cited by PubMed Abstract: Transthyretin (TTR) is a causative protein of TTR amyloidosis (ATTR amyloidosis), a general term for diseases characterized by deposition of TTR amyloid fibrils in specific organs. ATTR amyloidosis can be ameliorated by stabilization of the TTR tetramer through the binding of small molecules. Here, we show that the clinical anthelmintic drugs bithionol () and triclabendazole () potently inhibit aggregation of the amyloidogenic variant V30M-TTR. A competitive binding assay using a fluorescence probe showed that the binding affinity of with V30M-TTR was significantly higher than that of the first-in-class drug tafamidis (), and the binding affinity of was similar to that of . The crystallographic and thermodynamic analysis revealed that efficiently occupied the halogen-binding grooves of TTR, resulting in the favorable binding entropy. Multifaceted studies of anthelmintic drugs have the potential to reposition these drugs as ATTR amyloidosis inhibitors. PubMed: 34547896DOI: 10.1021/acs.jmedchem.1c00823 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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