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- PDB-8ve4: Unliganded human transthyretin in the frayed conformation -

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Basic information

Entry
Database: PDB / ID: 8ve4
TitleUnliganded human transthyretin in the frayed conformation
ComponentsTransthyretin
KeywordsTRANSPORT PROTEIN / Amyloidosis
Function / homology
Function and homology information


Defective visual phototransduction due to STRA6 loss of function / negative regulation of glomerular filtration / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / molecular sequestering activity / phototransduction, visible light / Non-integrin membrane-ECM interactions / retinoid metabolic process / Retinoid metabolism and transport / hormone activity ...Defective visual phototransduction due to STRA6 loss of function / negative regulation of glomerular filtration / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / molecular sequestering activity / phototransduction, visible light / Non-integrin membrane-ECM interactions / retinoid metabolic process / Retinoid metabolism and transport / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation / extracellular space / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
Transthyretin, conserved site / Transthyretin signature 2. / Transthyretin, thyroxine binding site / Transthyretin signature 1. / Transthyretin / Transthyretin/hydroxyisourate hydrolase / Transthyretin/hydroxyisourate hydrolase domain / Transthyretin/hydroxyisourate hydrolase domain superfamily / HIUase/Transthyretin family
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsBasanta, B. / Nugroho, K. / Yan, N. / Kline, G.M. / Tsai, F.J. / Wu, M. / Kelly, J.W. / Lander, G.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM142196 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)AG067594 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: The conformational landscape of human transthyretin revealed by cryo-EM.
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 /
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.
History
DepositionDec 18, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 5, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.2May 28, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transthyretin
B: Transthyretin
C: Transthyretin
D: Transthyretin


Theoretical massNumber of molelcules
Total (without water)55,6344
Polymers55,6344
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Transthyretin / ATTR / Prealbumin / TBPA


Mass: 13908.557 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTR, PALB / Production host: Escherichia coli (E. coli) / References: UniProt: P02766
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Transthyretin / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.05553 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.6
Buffer component
IDConc.NameFormulaBuffer-ID
1100 mMPotassium ChlorideKCl1
28.66 mMPotassium PhosphateK2HPO41
31.34 mMPotassium PhosphateKH2PO41
41 mMEDTAC10H16N2O81
SpecimenConc.: 0.85 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: The graphene grids were treated with UV/ozone using the UVOCS T10xT10 system. A 10-minute warmup run was performed immediately prior to inserting and treating grids for 4 minutes.
Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 279 K
Details: 3 uL of sample were applied onto the graphene side of the grid after it was mounted on the plunger (always at the same height), and immediately blotted for 4 seconds by holding a 1 x 6 cm ...Details: 3 uL of sample were applied onto the graphene side of the grid after it was mounted on the plunger (always at the same height), and immediately blotted for 4 seconds by holding a 1 x 6 cm piece of Whatman 1 filter paper parallel to the grid, in full contact. Timing was kept with the help of a metronome. The blotting countdown was started after the blotted liquid spot on the filter paper stopped spreading and the grid was plunged in liquid ethane at the same time the blotting paper was pulled back, in a single motion.

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 73000 X / Calibrated magnification: 88968 X / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm / Calibrated defocus min: 500 nm / Calibrated defocus max: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 85 K / Temperature (min): 78 K
Image recordingAverage exposure time: 6.8 sec. / Electron dose: 52 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 3739
Image scansSampling size: 5 µm / Width: 3838 / Height: 3710 / Movie frames/image: 50 / Used frames/image: 1-50

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Processing

EM software
IDNameVersionCategory
2PHENIX1.19.2_4158:model refinement
3Leginon3.6image acquisition
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 202700 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 89.61 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00233238
ELECTRON MICROSCOPYf_angle_d0.4844467
ELECTRON MICROSCOPYf_chiral_restr0.0452538
ELECTRON MICROSCOPYf_plane_restr0.0056566
ELECTRON MICROSCOPYf_dihedral_angle_d3.6941488

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