7W9R
Crystal structure of V30M-TTR in complex with naringenin derivative-18
Summary for 7W9R
| Entry DOI | 10.2210/pdb7w9r/pdb |
| Descriptor | Transthyretin, (2~{R})-2-[3,5-bis(chloranyl)-4-oxidanyl-phenyl]-5,7-bis(oxidanyl)-2,3-dihydrochromen-4-one (3 entities in total) |
| Functional Keywords | amyloidosis, complex, inhibitor, thyroxine, transport protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 35367.45 |
| Authors | Katayama, W.,Shimane, A.,Nabeshima, Y.,Yokoyama, T.,Mizuguchi, M. (deposition date: 2021-12-10, release date: 2022-12-14, Last modification date: 2023-11-29) |
| Primary citation | Mizuguchi, M.,Nakagawa, Y.,Inui, K.,Katayama, W.,Sawai, Y.,Shimane, A.,Kitakami, R.,Okada, T.,Nabeshima, Y.,Yokoyama, T.,Kanamitsu, K.,Nakagawa, S.,Toyooka, N. Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis. J.Med.Chem., 65:16218-16233, 2022 Cited by PubMed Abstract: Misfolding and aggregation of transthyretin are implicated in the fatal systemic disease known as transthyretin amyloidosis. Here, we report the development of a naringenin derivative bearing two chlorine atoms that will be efficacious for preventing aggregation of transthyretin in the eye. The amyloid inhibitory activity of the naringenin derivative was as strong as that of tafamidis, which is the first therapeutic agent targeting transthyretin in the plasma. X-ray crystal structures of the compounds in complex with transthyretin demonstrated that the naringenin derivative with one chlorine bound to the thyroxine-binding site of transthyretin in the forward mode and that the derivative with two chlorines bound to it in the reverse mode. An ex vivo competitive binding assay showed that naringenin derivatives exhibited more potent binding than tafamidis in the plasma. Furthermore, an in vivo pharmacokinetic study demonstrated that the dichlorinated derivative was significantly delivered to the eye. PubMed: 36472374DOI: 10.1021/acs.jmedchem.2c00511 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.997 Å) |
Structure validation
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