9JIQ

Crystal structure of V30M-TTR in complex with bromoxynil

This is a non-PDB format compatible entry.

Summary for 9JIQ

• Entry DOI: 10.2210/pdb9jiq/pdb
• Descriptor: Transthyretin, bromoxynil (3 entities in total)
• Functional Keywords: amyloidosis, tyroxine, inhibitor, stabilizer, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 35792.82

Authors

Yokoyama, T. (deposition date: 2024-09-12, release date: 2025-01-22, Last modification date: 2025-02-05)

Primary citation

Yokoyama, T.,Fujiwara, S.,Nishikubo, K.,Mizuguchi, M.,Nabeshima, Y.,Toyooka, N.,Okada, T.,Nakagawa, Y.
Repurposing of Agrochemicals as ATTRv Amyloidosis Inhibitors.
J.Med.Chem., 68:1572-1586, 2025

PubMed Abstract: Transthyretin (TTR), a plasma protein, undergoes transformation into amyloid fibers, leading to ATTRv amyloidosis, a disease characterized by organ deposition of TTR amyloid fibrils and subsequent organ failure. Developing compounds that bind and kinetically stabilize TTR is a crucial strategy in the treatment of ATTRv amyloidosis. In this study, we narrowed 651 pesticide-related compounds down to 14 possible TTR binders through in silico screening; subsequent in vitro analysis revealed that 7 of them exhibited amyloid fibril formation inhibition activity. The herbicide components bromoxynil () and ioxynil () showed especially high ligand efficiency and efficiently inhibited amyloid fibril formation of amyloidogenic V30M-TTR. Additionally, aclonifen () exhibited moderate fibril formation inhibition activity, but showed selective binding to TTR comparable to that of tafamidis. While improvement is needed to the selective TTR-binding or fibril formation inhibition activity, the compounds identified herein are promising lead candidates for the development of ATTRv amyloidosis therapeutics.

PubMed: 39761163
DOI: 10.1021/acs.jmedchem.4c02221

Experimental method

X-RAY DIFFRACTION (1.78 Å)