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- PDB-6b5h: ALDH1A2 liganded with NAD and 1-(4-cyanophenyl)-N-(3-fluorophenyl... -

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Basic information

Entry
Database: PDB / ID: 6b5h
TitleALDH1A2 liganded with NAD and 1-(4-cyanophenyl)-N-(3-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole-4-carboxamide (compound CM121)
ComponentsRetinal dehydrogenase 2
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 / retinoic acid receptor signaling pathway involved in somitogenesis / 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 ...determination of bilateral symmetry / retinoic acid receptor signaling pathway involved in somitogenesis / 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 / cardiac muscle tissue development / retinal binding / response to vitamin A / pancreas development / embryonic forelimb morphogenesis / retinal dehydrogenase activity / neural tube development / retinoic acid metabolic process / retinol metabolic process / midgut development / blood vessel development / face development / heart morphogenesis / response to retinoic acid / cellular response to retinoic acid / liver development / kidney development / response to cytokine / 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, N-terminal / Aldehyde dehydrogenase, C-terminal / Aldehyde/histidinol dehydrogenase
Similarity search - Domain/homology
Chem-CU4 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Retinal dehydrogenase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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
DepositionSep 29, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Retinal dehydrogenase 2
B: Retinal dehydrogenase 2
C: Retinal dehydrogenase 2
D: Retinal dehydrogenase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,17812
Polymers216,6824
Non-polymers4,4968
Water6,882382
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24650 Å2
ΔGint-104 kcal/mol
Surface area58690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.850, 141.860, 164.750
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
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 / Plasmid: pET28 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21Star(DE3) / References: UniProt: O94788, retinal dehydrogenase
#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical
ChemComp-CU4 / 1-(4-cyanophenyl)-N-(3-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1H-pyrazole-4-carboxamide


Mass: 460.480 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H17FN4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 382 / Source method: isolated from a natural source / Formula: H2O

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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: 2.29 Å3/Da / Density % sol: 46.24 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 40 mg/mL ALDH1A2, 0.2 M sodium citrate tribasic dehydrate, 25% w/v PEG3350, 1.3 mM CM121, 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: Nov 8, 2016
RadiationMonochromator: Rosenbaum-Rock double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→72.818 Å / Num. obs: 88789 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 7.426 % / Biso Wilson estimate: 37.92 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.079 / Rrim(I) all: 0.085 / Χ2: 0.975 / Net I/σ(I): 17.79 / Num. measured all: 659332 / Scaling rejects: 33
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
2.3-2.47.5620.6423.767931710529104890.8920.68999.6
2.4-2.67.5530.4295.4412460116525164970.9510.4699.8
2.6-2.87.5480.2727.989159912166121350.9780.29299.7
2.8-37.5310.17211.6768879916591460.990.18599.8
3-3.57.4590.08919.8511025214803147820.9970.09699.9
3.5-47.3310.05231.2861250836183550.9990.05699.9
4-57.2280.0439.5660390836083550.9990.04399.9
5-67.1710.03937.9526682372337210.9990.04299.9
6-77.0820.03839.1913590192019190.9990.04199.9
7-86.9890.03242.197639109510930.9990.03599.8
8-106.9260.03244.537487108710810.9990.03499.4
10-206.4940.03343.166845105810540.9990.03699.6
20-72.8184.9440.03931.368011731620.9990.04493.6

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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 6ALJ

6alj


Resolution: 2.3→72.818 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 28.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2635 1775 2 %
Rwork0.2056 86980 -
obs0.2067 88755 99.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 90.28 Å2 / Biso mean: 42.332 Å2 / Biso min: 16.28 Å2
Refinement stepCycle: final / Resolution: 2.3→72.818 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15244 0 308 382 15934
Biso mean--53.7 38.87 -
Num. residues----1972
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00215907
X-RAY DIFFRACTIONf_angle_d0.54121572
X-RAY DIFFRACTIONf_chiral_restr0.0412336
X-RAY DIFFRACTIONf_plane_restr0.0032808
X-RAY DIFFRACTIONf_dihedral_angle_d6.0999364
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.36220.31961350.259166266761100
2.3622-2.43170.33451340.249865896723100
2.4317-2.51020.33881360.24266236759100
2.5102-2.59990.29941340.239866066740100
2.5999-2.70410.31811350.241566176752100
2.7041-2.82710.3121360.240866566792100
2.8271-2.97620.2831360.225366276763100
2.9762-3.16260.29441360.22666866822100
3.1626-3.40680.28061360.213966886824100
3.4068-3.74970.24991370.201267066843100
3.7497-4.29220.2491380.185967466884100
4.2922-5.40750.22241390.169367956934100
5.4075-72.85490.22181430.18847015715899

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