8IG1
Crystal structure of wild-type transthyretin in complex with rafoxanide
Summary for 8IG1
| Entry DOI | 10.2210/pdb8ig1/pdb |
| Descriptor | Transthyretin, ~{N}-[3-chloranyl-4-(4-chloranylphenoxy)phenyl]-3,5-bis(iodanyl)-2-oxidanyl-benzamide, SODIUM ION, ... (4 entities in total) |
| Functional Keywords | t4 carrier, transporter, amyloidosis, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 35919.04 |
| Authors | Yokoyama, T. (deposition date: 2023-02-20, release date: 2023-08-16, Last modification date: 2023-11-15) |
| Primary citation | Yokoyama, T.,Mizuguchi, M.,Nabeshima, Y.,Nakagawa, Y.,Okada, T.,Toyooka, N.,Kusaka, K. Rafoxanide, a salicylanilide anthelmintic, interacts with human plasma protein transthyretin. Febs J., 290:5158-5170, 2023 Cited by PubMed Abstract: Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T for binding to TTR should be carefully studied, these small molecules can also serve as anti-ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU-approved anthelmintic drug for domesticated animals, binds to the T -binding site of TTR. An intrinsic fluorescence quenching assay showed that rafoxanide also binds to the thyroid hormone-related proteins, including serum albumin and thyroid hormone receptor β. Rafoxanide strongly inhibited TTR amyloidogenesis in fibrillization assay, but the binding of rafoxanide to TTR was interfered with in human plasma, probably due to interactions with thyroid hormone-related proteins. Protein crystallography provided clues for the optimization of binding affinity and selectivity. Our findings emphasize the importance of considering rafoxanide as both a possible thyroid-disrupting chemical and a lead compound for the development of new ATTR amyloidosis inhibitors. PubMed: 37522420DOI: 10.1111/febs.16915 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.451 Å) |
Structure validation
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