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- PDB-8u52: Co-crystal structure of human transthyretin conjugated to the sti... -

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Basic information

Entry
Database: PDB / ID: 8u52
TitleCo-crystal structure of human transthyretin conjugated to the stilbene substructure derived from reaction with the fluorogenic covalent kinetic stabilizer A2
ComponentsTransthyretin
KeywordsTRANSPORT PROTEIN / transthyretin / amyloidosis / stabilizer / covalent / fluorogenic
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
Chem-1W4 / Transthyretin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsYan, N.L. / Nugroho, K. / Kline, G.M. / Basanta, B. / Lander, G.C. / Wilson, I.A. / Kelly, J.W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)5R01DK046335-32 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
DepositionSep 11, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transthyretin
B: Transthyretin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,3984
Polymers27,5552
Non-polymers8432
Water2,954164
1
A: Transthyretin
B: Transthyretin
hetero molecules

A: Transthyretin
B: Transthyretin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7968
Polymers55,1094
Non-polymers1,6864
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Unit cell
Length a, b, c (Å)42.960, 85.201, 63.751
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-201-

1W4

21A-201-

1W4

31A-201-

1W4

41B-201-

1W4

51B-201-

1W4

61B-201-

1W4

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Components

#1: Protein Transthyretin / ATTR / Prealbumin / TBPA


Mass: 13777.360 Da / Num. of mol.: 2
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
#2: Chemical ChemComp-1W4 / S-(4-fluorophenyl) 3-(dimethylamino)-5-[(E)-2-(4-hydroxy-3,5-dimethylphenyl)ethenyl]benzenecarbothioate


Mass: 421.527 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24FNO2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 164 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.12 Å3/Da / Density % sol: 41.9 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: The WT-TTR was concentrated to 4 mg/mL in 10 mM sodium phosphate, 100 mM KCl, at pH 7.6 and co-crystallized at room temperature using the vapor diffusion sitting drop method.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Dec 20, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.5→42.64 Å / Num. obs: 36591 / % possible obs: 95.7 % / Redundancy: 12.4 % / Biso Wilson estimate: 16 Å2 / CC1/2: 1 / Rpim(I) all: 0.008 / Rsym value: 0.029 / Net I/σ(I): 42.8
Reflection shellResolution: 1.5→1.58 Å / Mean I/σ(I) obs: 4.9 / Num. unique obs: 4326 / CC1/2: 0.94 / Rpim(I) all: 0.136 / Rsym value: 0.411

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→42.64 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.202 / SU ML: 0.045 / Cross valid method: THROUGHOUT / ESU R: 0.071 / ESU R Free: 0.073 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19389 1844 5 %RANDOM
Rwork0.16483 ---
obs0.16629 34712 95.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.971 Å2
Baniso -1Baniso -2Baniso -3
1-0.65 Å20 Å2-0 Å2
2---0.69 Å20 Å2
3---0.04 Å2
Refinement stepCycle: 1 / Resolution: 1.5→42.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1778 0 44 164 1986
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0460.0131933
X-RAY DIFFRACTIONr_bond_other_d0.0040.0171741
X-RAY DIFFRACTIONr_angle_refined_deg2.891.6822657
X-RAY DIFFRACTIONr_angle_other_deg1.6041.5944047
X-RAY DIFFRACTIONr_dihedral_angle_1_deg14.7835.179252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.67122.75987
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.49815295
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.571158
X-RAY DIFFRACTIONr_chiral_restr0.1040.2257
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.022410
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02420
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.5592.065941
X-RAY DIFFRACTIONr_mcbond_other2.5582.065942
X-RAY DIFFRACTIONr_mcangle_it3.7013.0861179
X-RAY DIFFRACTIONr_mcangle_other3.7013.091180
X-RAY DIFFRACTIONr_scbond_it4.5322.636992
X-RAY DIFFRACTIONr_scbond_other4.532.635993
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.7373.7431470
X-RAY DIFFRACTIONr_long_range_B_refined8.62325.9952092
X-RAY DIFFRACTIONr_long_range_B_other8.63126.0232088
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.5→1.539 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 94 -
Rwork0.235 1906 -
obs--71.53 %

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