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- PDB-4d7b: Structure of human transthyretin in complex with Tolcapone -

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Basic information

Entry
Database: PDB / ID: 4d7b
TitleStructure of human transthyretin in complex with Tolcapone
ComponentsTRANSTHYRETIN
KeywordsTRANSPORT PROTEIN / AMYLOIDOGENESIS
Function / homology
Function and homology information


Retinoid cycle disease events / The canonical retinoid cycle in rods (twilight vision) / thyroid hormone binding / purine nucleobase metabolic process / Non-integrin membrane-ECM interactions / Retinoid metabolism and transport / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation ...Retinoid cycle disease events / The canonical retinoid cycle in rods (twilight vision) / thyroid hormone binding / purine nucleobase metabolic process / Non-integrin membrane-ECM interactions / 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/hydroxyisourate hydrolase domain / 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 ...Transthyretin/hydroxyisourate hydrolase domain / 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 / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Tolcapone / Transthyretin
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.15 Å
AuthorsGallego, P. / Sant'anna, R.O. / Ventura, S. / Reverter, D.
CitationJournal: Nat.Commun. / Year: 2016
Title: Repositioning Tolcapone as a Potent Inhibitor of Transthyretin Amyloidogenesis and its Associated Cellular Toxicity
Authors: Reverter, D. / Gallego, P. / Santana, R. / Ventura, S.
History
DepositionNov 21, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 20, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2016Group: Database references
Revision 1.2Mar 2, 2016Group: Database references
Revision 1.3May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_struct_special_symmetry / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)28,3644
Polymers27,8172
Non-polymers5462
Water3,981221
1
A: TRANSTHYRETIN
B: TRANSTHYRETIN
hetero molecules

A: TRANSTHYRETIN
B: TRANSTHYRETIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7278
Polymers55,6344
Non-polymers1,0934
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area6420 Å2
ΔGint-40.5 kcal/mol
Surface area19170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.112, 43.807, 65.852
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-1126-

TCW

21A-1126-

TCW

31B-1126-

TCW

41A-2095-

HOH

51B-2114-

HOH

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Components

#1: Protein TRANSTHYRETIN / / ATTR / PREALBUMIN / TBPA


Mass: 13908.557 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P02766
#2: Chemical ChemComp-TCW / Tolcapone / (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone / Tolcapone


Mass: 273.241 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H11NO5 / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 221 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.18 Å3/Da / Density % sol: 43.6 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.9792
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.15→43.81 Å / Num. obs: 86971 / % possible obs: 98.7 % / Observed criterion σ(I): 2 / Redundancy: 6.2 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 16
Reflection shellResolution: 1.15→1.21 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 3.6 / % possible all: 96.6

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.15→65.85 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.947 / SU B: 1.207 / SU ML: 0.026 / Cross valid method: THROUGHOUT / ESU R: 0.037 / ESU R Free: 0.038 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.20059 4348 5 %RANDOM
Rwork0.17094 ---
obs0.17245 82563 99.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.517 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--1.44 Å20 Å2
3----1.44 Å2
Refinement stepCycle: LAST / Resolution: 1.15→65.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1792 0 40 221 2053
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0320.0191997
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.4171.9522752
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7665259
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.26623.7580
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.90415302
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.453159
X-RAY DIFFRACTIONr_chiral_restr0.1690.2307
X-RAY DIFFRACTIONr_gen_planes_refined0.0160.0211567
X-RAY DIFFRACTIONr_gen_planes_other
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr12.03831985
X-RAY DIFFRACTIONr_sphericity_free36.297565
X-RAY DIFFRACTIONr_sphericity_bonded24.82652088
LS refinement shellResolution: 1.149→1.178 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 248 -
Rwork0.293 5405 -
obs--92.69 %
Refinement TLS params.

T23: -0.0005 Å2 / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.12570.0845-0.05760.077-0.03510.0747-0.0045-0.0111-0.0011-0.0016-0.0002-0.0042-0.0006-0.00640.00470.02320.00070.00070.01230.0331-12.96420.631-6.4572
20.1093-0.06590.08890.0446-0.06620.1293-0.00690.0118-0.00020.00590.001-0.0041-0.0031-0.01310.0060.0240.00010.00010.01540.0339-12.8529-1.4368-26.4952
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1B10 - 125
2X-RAY DIFFRACTION2A10 - 125

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