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- PDB-8pma: Crystal structure of human V30M transthyretin in complex with PIT... -

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Basic information

Entry
Database: PDB / ID: 8pma
TitleCrystal structure of human V30M transthyretin in complex with PITB (Pharmacokinetically Improved TTR Binder)
ComponentsTransthyretin
KeywordsTRANSPORT PROTEIN / Aggregation / Inhibitor / Amyloid
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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsVarejao, N. / Pinheiro, F. / Pallares, I. / Ventura, S. / Reverter, D.
Funding support Spain, 1items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)PGC2018-098423-B-I00 Spain
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties.
Authors: Pinheiro, F. / Varejao, N. / Sanchez-Morales, A. / Bezerra, F. / Navarro, S. / Velazquez-Campoy, A. / Busque, F. / Almeida, M.R. / Alibes, R. / Reverter, D. / Pallares, I. / Ventura, S.
History
DepositionJun 28, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 8, 2024Provider: repository / Type: Initial release

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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)28,2334
Polymers27,6192
Non-polymers6142
Water4,288238
1
A: Transthyretin
B: Transthyretin
hetero molecules

A: Transthyretin
B: Transthyretin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,4678
Polymers55,2384
Non-polymers1,2294
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Unit cell
Length a, b, c (Å)44.058, 65.344, 85.214
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21221
Components on special symmetry positions
IDModelComponents
11A-201-

ZP2

21A-201-

ZP2

31B-201-

ZP2

41B-201-

ZP2

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Components

#1: Protein Transthyretin / ATTR / Prealbumin / TBPA


Mass: 13809.426 Da / Num. of mol.: 2 / Mutation: V30M
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-ZP2 / (3-fluoranyl-5-oxidanyl-phenyl)-(3-methoxy-5-nitro-4-oxidanyl-phenyl)methanone / Pharmacokinetically Improved TTR Binder (PITB)


Mass: 307.231 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H10FNO6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 238 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.19 Å3/Da / Density % sol: 43.84 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 0.1M HEPES pH7.0, 0.2M CaCl2, 20% PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.979264 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 4, 2022
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979264 Å / Relative weight: 1
ReflectionResolution: 1.2→44.06 Å / Num. obs: 76676 / % possible obs: 98.7 % / Redundancy: 12.8 % / CC1/2: 1 / Net I/σ(I): 28.3
Reflection shellResolution: 1.2→1.22 Å / Num. unique obs: 3798 / CC1/2: 0.777

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Processing

Software
NameVersionClassification
PHENIX(1.17.1_3660: ???)refinement
XDSdata reduction
Aimless0.7.7data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.2→39.14 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2008 3868 5.05 %
Rwork0.1858 --
obs0.1866 76542 98.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.2→39.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1794 0 44 243 2081
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051940
X-RAY DIFFRACTIONf_angle_d0.7672658
X-RAY DIFFRACTIONf_dihedral_angle_d10.758267
X-RAY DIFFRACTIONf_chiral_restr0.084292
X-RAY DIFFRACTIONf_plane_restr0.007342
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.210.25591480.2672578X-RAY DIFFRACTION100
1.21-1.230.37381260.3342580X-RAY DIFFRACTION98
1.23-1.250.27911440.25422578X-RAY DIFFRACTION100
1.25-1.260.28131640.25662592X-RAY DIFFRACTION100
1.26-1.280.23541470.23512561X-RAY DIFFRACTION100
1.28-1.30.25531380.25922604X-RAY DIFFRACTION100
1.3-1.320.31111470.24942579X-RAY DIFFRACTION100
1.32-1.340.2621430.22632600X-RAY DIFFRACTION100
1.34-1.370.21761360.21212615X-RAY DIFFRACTION100
1.37-1.390.24531240.20792628X-RAY DIFFRACTION100
1.39-1.420.24311470.212619X-RAY DIFFRACTION100
1.42-1.450.25691240.20982595X-RAY DIFFRACTION100
1.45-1.480.24641460.20952599X-RAY DIFFRACTION100
1.48-1.510.24471420.20542632X-RAY DIFFRACTION100
1.51-1.550.20871290.19252622X-RAY DIFFRACTION100
1.55-1.590.20141560.18572602X-RAY DIFFRACTION100
1.59-1.640.17241540.17972604X-RAY DIFFRACTION100
1.64-1.690.19651390.17972615X-RAY DIFFRACTION100
1.69-1.750.19991390.19132620X-RAY DIFFRACTION100
1.75-1.820.20181470.18992628X-RAY DIFFRACTION100
1.82-1.90.19851440.18022606X-RAY DIFFRACTION100
1.93-2.010.1915970.17132052X-RAY DIFFRACTION100
2.01-2.130.17571390.16942657X-RAY DIFFRACTION100
2.13-2.30.1721010.17392339X-RAY DIFFRACTION87
2.3-2.530.20751540.18582667X-RAY DIFFRACTION100
2.53-2.890.22271100.18732727X-RAY DIFFRACTION100
2.89-3.640.18141270.1732731X-RAY DIFFRACTION100
3.64-39.140.19031560.17932844X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 21.6171 Å / Origin y: -16.1133 Å / Origin z: -12.6355 Å
111213212223313233
T0.1453 Å20.0025 Å20.0011 Å2-0.1677 Å2-0.0077 Å2--0.1341 Å2
L1.0881 °20.3241 °20.064 °2-0.7714 °2-0.1155 °2--0.8513 °2
S-0.0238 Å °0.2327 Å °-0.0572 Å °-0.0383 Å °0.0524 Å °-0.0224 Å °0.0219 Å °0.0131 Å °-0.0202 Å °
Refinement TLS groupSelection details: all

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