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- PDB-6alj: ALDH1A2 liganded with NAD and compound WIN18,446 -

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Basic information

Entry
Database: PDB / ID: 6alj
TitleALDH1A2 liganded with NAD and compound WIN18,446
ComponentsAldehyde dehydrogenase 1A2
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / RETINOIC ACID SIGNALING / MALE CONTRACEPTION / DRUG DISCOVERY / DRUG DEVELOPMENT / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


determination of bilateral symmetry / regulation of vascular endothelial cell proliferation / 9-cis-retinoic acid biosynthetic process / 3-chloroallyl aldehyde dehydrogenase activity / retinoic acid biosynthetic process / retinal dehydrogenase / ureter maturation / embryonic camera-type eye development / morphogenesis of embryonic epithelium / pituitary gland development ...determination of bilateral symmetry / regulation of vascular endothelial cell proliferation / 9-cis-retinoic acid biosynthetic process / 3-chloroallyl aldehyde dehydrogenase activity / retinoic acid biosynthetic process / retinal dehydrogenase / ureter maturation / embryonic camera-type eye development / morphogenesis of embryonic epithelium / pituitary gland development / RA biosynthesis pathway / proximal/distal pattern formation / vitamin A metabolic process / neural crest cell development / retinal metabolic process / hindbrain development / embryonic digestive tract development / aldehyde dehydrogenase (NAD+) activity / retinal binding / response to vitamin A / embryonic forelimb morphogenesis / pancreas development / retinal dehydrogenase activity / retinoic acid metabolic process / cardiac muscle tissue development / retinol metabolic process / neural tube development / anterior/posterior pattern specification / midgut development / blood vessel development / face development / retinoic acid receptor signaling pathway / response to retinoic acid / heart morphogenesis / cellular response to retinoic acid / liver development / response to cytokine / kidney development / lung development / neuron differentiation / response to estradiol / protein homotetramerization / cell population proliferation / positive regulation of apoptotic process / negative regulation of cell population proliferation / positive regulation of cell population proliferation / positive regulation of gene expression / perinuclear region of cytoplasm / cytosol / cytoplasm
Similarity search - Function
Aldehyde dehydrogenase, glutamic acid active site / Aldehyde dehydrogenases glutamic acid active site. / Aldehyde dehydrogenase, cysteine active site / Aldehyde dehydrogenases cysteine active site. / Aldehyde dehydrogenase domain / Aldehyde dehydrogenase family / Aldehyde dehydrogenase, C-terminal / Aldehyde dehydrogenase, N-terminal / Aldehyde/histidinol dehydrogenase
Similarity search - Domain/homology
N,N'-(octane-1,8-diyl)bis(2,2-dichloroacetamide) / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Retinal dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsChen, Y. / Zhu, J.-Y. / Schonbrunn, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)HHSN275201300017C United States
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)U54HD04245 United States
CitationJournal: ACS Chem. Biol. / Year: 2018
Title: Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors.
Authors: Chen, Y. / Zhu, J.Y. / Hong, K.H. / Mikles, D.C. / Georg, G.I. / Goldstein, A.S. / Amory, J.K. / Schonbrunn, E.
History
DepositionAug 8, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 10, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Database references / Category: citation / Item: _citation.title / _citation.year
Revision 1.2Mar 28, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aldehyde dehydrogenase 1A2
B: Aldehyde dehydrogenase 1A2
C: Aldehyde dehydrogenase 1A2
D: Aldehyde dehydrogenase 1A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)220,80112
Polymers216,6824
Non-polymers4,1188
Water37,3992076
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24610 Å2
ΔGint-95 kcal/mol
Surface area58260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.960, 139.820, 84.900
Angle α, β, γ (deg.)90.000, 94.070, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Aldehyde dehydrogenase 1A2 / Retinal dehydrogenase 2 / RalDH2 / Aldehyde dehydrogenase family 1 member A2 / Retinaldehyde- ...Retinal dehydrogenase 2 / RalDH2 / Aldehyde dehydrogenase family 1 member A2 / Retinaldehyde-specific dehydrogenase type 2 / RALDH(II)


Mass: 54170.602 Da / Num. of mol.: 4 / Fragment: UNP residues 26-518
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH1A2, RALDH2 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21Star (DE3) / References: UniProt: O94788, retinal dehydrogenase
#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical
ChemComp-CW2 / N,N'-(octane-1,8-diyl)bis(2,2-dichloroacetamide)


Mass: 366.111 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H20Cl4N2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2076 / Source method: isolated from a natural source / Formula: H2O
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: 2.24 Å3/Da / Density % sol: 45.2 %
Crystal growTemperature: 291.1 K / Method: vapor diffusion, hanging drop
Details: 40 MG/ML ALDH1A2, 0.2 M sodium citrate tribasic dehydrate, 20% w/v polyethylene glycol 3,350, 1.3 MM WIN18,446 and 10%DMSO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 24, 2016
RadiationMonochromator: ROSENBAUM-ROCK DOUBLE-CRYSTAL si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.89→40.831 Å / Num. obs: 150515 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 3.703 % / Biso Wilson estimate: 16.11 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.066 / Rrim(I) all: 0.078 / Χ2: 1.031 / Net I/σ(I): 16.26 / Num. measured all: 557355 / Scaling rejects: 67
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.89-23.3230.3125.047849823703236250.8990.37199.7
2-2.23.8190.198.7112097731779316810.9690.22199.7
2.2-2.43.810.12312.278399422117220460.9850.14499.7
2.4-2.63.8020.09315.155987515830157480.9910.10899.5
2.6-2.83.7780.07318.264365011639115540.9930.08599.3
2.8-33.7620.05921.1332582876286600.9950.06998.8
3-43.7070.03828.27989422014215510.9980.04497.9
4-53.710.02834.6428417788676600.9980.03397.1
5-63.7190.02933.312449348533470.9980.03496
6-73.6970.03133.096359178317200.9980.03696.5
7-83.6980.02735.9235469919590.9980.03196.8
8-103.6840.02437.73357710109710.9990.02996.1
10-203.6350.02637.431959348790.9990.03194.1
20-40.83130.02529.363421371140.9990.0383.2

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Processing

Software
NameVersionClassification
PHENIX1.11.1-2575_2575refinement
XSCALEdata scaling
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1BI9

1bi9


Resolution: 1.89→40.831 Å / SU ML: 0.15 / Cross valid method: NONE / σ(F): 1.38 / Phase error: 16.7 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1769 1505 1 %
Rwork0.1368 148985 -
obs0.1372 150490 98.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 60.6 Å2 / Biso mean: 17.4426 Å2 / Biso min: 5.83 Å2
Refinement stepCycle: final / Resolution: 1.89→40.831 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15244 0 176 2076 17496
Biso mean--21.68 26.93 -
Num. residues----1972
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0115898
X-RAY DIFFRACTIONf_angle_d1.02821549
X-RAY DIFFRACTIONf_chiral_restr0.0642353
X-RAY DIFFRACTIONf_plane_restr0.0062810
X-RAY DIFFRACTIONf_dihedral_angle_d6.66813065
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.89-1.9510.22161380.17471359913737100
1.951-2.02070.19091370.14821361113748100
2.0207-2.10160.18781380.13971361513753100
2.1016-2.19730.17661370.13851357313710100
2.1973-2.31310.18831370.13881362013757100
2.3131-2.4580.18731380.14051359613734100
2.458-2.64770.18541380.1438136501378899
2.6477-2.91410.21291370.148135601369799
2.9141-3.33560.16531350.1391134491358498
3.3356-4.20190.15751360.1181133841352098
4.2019-40.8410.15131340.1274133281346296

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