8VE3

Unliganded human transthyretin in the compressed conformation

8VE3 の概要

• エントリーDOI: 10.2210/pdb8ve3/pdb
• EMDBエントリー: 43163
• 分子名称: Transthyretin (1 entity in total)
• 機能のキーワード: amyloidosis, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 55634.23

構造登録者

Basanta, B.,Nugroho, K.,Yan, N.,Kline, G.M.,Tsai, F.J.,Wu, M.,Kelly, J.W.,Lander, G.C. (登録日: 2023-12-18, 公開日: 2024-06-05, 最終更新日: 2025-05-28)

主引用文献

Basanta, B.,Nugroho, K.,Yan, N.L.,Kline, G.M.,Powers, E.T.,Tsai, F.J.,Wu, M.,Hansel-Harris, A.,Chen, J.S.,Forli, S.,Kelly, J.W.,Lander, G.C.
The conformational landscape of human transthyretin revealed by cryo-EM.
Nat.Struct.Mol.Biol., 32:876-883, 2025

PubMed Abstract: Transthyretin (TTR) is a natively tetrameric thyroxine transporter in blood and cerebrospinal fluid whose misfolding and aggregation causes TTR amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndamax) as a stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency approved for the treatment of TTR amyloidosis. Here we used cryo-EM to investigate the conformational landscape of this 55 kDa tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unobserved conformational states. These findings provide critical mechanistic insights into negatively cooperative ligand binding and the structural pathways responsible for TTR amyloidogenesis, underscoring the capacity of cryo-EM to identify pharmacological targets suppressed by the confines of the crystal lattice, opening uncharted territory in structure-based drug design.

PubMed: 39843982
DOI: 10.1038/s41594-024-01472-7

実験手法

ELECTRON MICROSCOPY (3.3 Å)