EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	The conformational landscape of human transthyretin revealed by cryo-EM.
ジャーナル・号・ページ	Nat Struct Mol Biol, Vol. 32, Issue 5, Page 876-883, Year 2025
掲載日	2025年1月22日
著者	Benjamin Basanta / Karina Nugroho / Nicholas L Yan / Gabriel M Kline / Evan T Powers / Felix J Tsai / Mengyu Wu / Althea Hansel-Harris / Jason S Chen / Stefano Forli / Jeffrey W Kelly / Gabriel C Lander /
PubMed 要旨	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 ...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.
リンク	Nat Struct Mol Biol / PubMed:39843982 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	1.5 - 4.1 Å
構造データ	43160 8ve0 EMDB-43160, PDB-8ve0: Human transthyretin covalently modified with A2-derived stilbene in the compressed conformation 手法: EM (単粒子) / 解像度: 3.1 Å 43161 8ve1 EMDB-43161, PDB-8ve1: Human transthyretin covalently modified with A2-derived stilbene in the canonical conformation 手法: EM (単粒子) / 解像度: 2.7 Å 43162 8ve2 EMDB-43162, PDB-8ve2: Unliganded human transthyretin in the canonical conformation 手法: EM (単粒子) / 解像度: 3.3 Å 43163 8ve3 EMDB-43163, PDB-8ve3: Unliganded human transthyretin in the compressed conformation 手法: EM (単粒子) / 解像度: 3.3 Å 43164 8ve4 EMDB-43164, PDB-8ve4: Unliganded human transthyretin in the frayed conformation 手法: EM (単粒子) / 解像度: 3.3 Å 43165 8ve5 EMDB-43165, PDB-8ve5: (Biarylamine-FT2-WT)1(C10A)3-human transthyretin in the compressed conformation 手法: EM (単粒子) / 解像度: 3.4 Å 43166 8ve6 EMDB-43166, PDB-8ve6: (Biarylamine-FT2-WT)1(C10A)3-human transthyretin in the frayed conformation 手法: EM (単粒子) / 解像度: 4.1 Å PDB-8u52: Co-crystal structure of human transthyretin conjugated to the stilbene substructure derived from reaction with the fluorogenic covalent kinetic stabilizer A2 手法: X-RAY DIFFRACTION / 解像度: 1.5 Å
化合物	ChemComp-1W4: S-(4-fluorophenyl) 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzenecarbothioate ChemComp-HOH: WATER ChemComp-1WZ: 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoic acid ChemComp-P2C: 2-[(3,5-DICHLORO-4-TRIOXIDANYLPHENYL)AMINO]BENZOIC ACID
由来	homo sapiens (ヒト)
キーワード	TRANSPORT PROTEIN / transthyretin / amyloidosis / stabilizer / covalent / fluorogenic