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- EMDB-43160: Human transthyretin covalently modified with A2-derived stilbene ... -

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Basic information

Entry
Database: EMDB / ID: EMD-43160
TitleHuman transthyretin covalently modified with A2-derived stilbene in the compressed conformation
Map dataCompressed A2 TTR map
Sample
  • Complex: Transthyretin
    • Protein or peptide: Transthyretin
  • Ligand: 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoic acid
KeywordsAmyloidosis / TRANSPORT PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBasanta B / Nugroho K / Yan N / Kline GM / Tsai FJ / Wu M / Kelly JW / Lander GC
Funding support United States, 2 items
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, 2023-
Header (metadata) releaseJan 31, 2024-
Map releaseJan 31, 2024-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43160.png

Downloads & links

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Map

FileDownload / File: emd_43160.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCompressed A2 TTR map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.56 Å/pix.
x 256 pix.
= 143.872 Å		0.56 Å/pix.
x 256 pix.
= 143.872 Å		0.56 Å/pix.
x 256 pix.
= 143.872 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.562 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0102
Minimum - Maximum-0.03350502 - 0.060491238
Average (Standard dev.)0.00008958092 (±0.0018322805)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 143.872 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43160_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Compressed A2 TTR half map 1

Fileemd_43160_half_map_1.map
AnnotationCompressed A2 TTR half map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Compressed A2 TTR half map 2

Fileemd_43160_half_map_2.map
AnnotationCompressed A2 TTR half map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Transthyretin

EntireName: Transthyretin
Components
  • Complex: Transthyretin
    • Protein or peptide: Transthyretin
  • Ligand: 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoic acid

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Supramolecule #1: Transthyretin

SupramoleculeName: Transthyretin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.136 KDa

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Macromolecule #1: Transthyretin

MacromoleculeName: Transthyretin / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.908557 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGPTGTGESK CPLMVKVLDA VRGSPAINVA VHVFRKAADD TWEPFASGKT SESGELHGLT TEEEFVEGIY KVEIDTKSYW KALGISPFH EHAEVVFTAN DSGPRRYTIA ALLSPYSYST TAVVTNPKE

UniProtKB: Transthyretin

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Macromolecule #2: 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]...

MacromoleculeName: 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoic acid
type: ligand / ID: 2 / Number of copies: 2 / Formula: 1WZ
Molecular weightTheoretical: 311.375 Da
Chemical component information

ChemComp-1WZ:
3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzoic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.41 mg/mL
BufferpH: 7.6
Component:
ConcentrationFormulaName
100.0 mMKClPotassium Chloride
8.66 mMK2HPO4Potassium Phosphate
1.34 mMKH2PO4Potassium Phosphate
1.0 mMC10H16N2O8EDTA
0.01 % w/vC14H28O6beta-octyl glucoside (BOG)
1.25 % v/vC2H6OSDMSO
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GRAPHENE / Support film - topology: CONTINUOUS / Pretreatment - Time: 240 sec. / Pretreatment - Atmosphere: OTHER
Details: 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 the grids for 4 minutes.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 279 K / Instrument: HOMEMADE PLUNGER
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 6 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 6 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

MicroscopeFEI TALOS ARCTICA
TemperatureMin: 78.0 K / Max: 85.0 K
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Number grids imaged: 1 / Number real images: 4536 / Average exposure time: 6.8 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 1.5 µm / Calibrated defocus min: 0.5 µm / Calibrated magnification: 88968 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 73000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

1ttr

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 105961
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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