Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	The conformational landscape of human transthyretin revealed by cryo-EM.
Journal, issue, pages	Nat Struct Mol Biol, Vol. 32, Issue 5, Page 876-883, Year 2025
Publish date	Jan 22, 2025
Authors	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 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 ...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.
External links	Nat Struct Mol Biol / PubMed:39843982 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	1.5 - 4.1 Å
Structure data	43160 8ve0 EMDB-43160, PDB-8ve0: Human transthyretin covalently modified with A2-derived stilbene in the compressed conformation Method: EM (single particle) / Resolution: 3.1 Å 43161 8ve1 EMDB-43161, PDB-8ve1: Human transthyretin covalently modified with A2-derived stilbene in the canonical conformation Method: EM (single particle) / Resolution: 2.7 Å 43162 8ve2 EMDB-43162, PDB-8ve2: Unliganded human transthyretin in the canonical conformation Method: EM (single particle) / Resolution: 3.3 Å 43163 8ve3 EMDB-43163, PDB-8ve3: Unliganded human transthyretin in the compressed conformation Method: EM (single particle) / Resolution: 3.3 Å 43164 8ve4 EMDB-43164, PDB-8ve4: Unliganded human transthyretin in the frayed conformation Method: EM (single particle) / Resolution: 3.3 Å 43165 8ve5 EMDB-43165, PDB-8ve5: (Biarylamine-FT2-WT)1(C10A)3-human transthyretin in the compressed conformation Method: EM (single particle) / Resolution: 3.4 Å 43166 8ve6 EMDB-43166, PDB-8ve6: (Biarylamine-FT2-WT)1(C10A)3-human transthyretin in the frayed conformation Method: EM (single particle) / Resolution: 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 Method: X-RAY DIFFRACTION / Resolution: 1.5 Å
Chemicals	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
Source	homo sapiens (human)
Keywords	TRANSPORT PROTEIN / transthyretin / amyloidosis / stabilizer / covalent / fluorogenic