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- PDB-7jwu: Crystal structure of human ALDH1A1 bound to compound (R)-28 -

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Basic information

Entry
Database: PDB / ID: 7jwu
TitleCrystal structure of human ALDH1A1 bound to compound (R)-28
ComponentsRetinal dehydrogenase 1
KeywordsCYTOSOLIC PROTEIN / Rossmann fold
Function / homology
Function and homology information


fructosamine catabolic process / 3-deoxyglucosone dehydrogenase activity / benzaldehyde dehydrogenase (NAD+) / benzaldehyde dehydrogenase (NAD+) activity / maintenance of lens transparency / retinal dehydrogenase / gamma-aminobutyric acid biosynthetic process / aminobutyraldehyde dehydrogenase / aminobutyraldehyde dehydrogenase (NAD+) activity / Fructose catabolism ...fructosamine catabolic process / 3-deoxyglucosone dehydrogenase activity / benzaldehyde dehydrogenase (NAD+) / benzaldehyde dehydrogenase (NAD+) activity / maintenance of lens transparency / retinal dehydrogenase / gamma-aminobutyric acid biosynthetic process / aminobutyraldehyde dehydrogenase / aminobutyraldehyde dehydrogenase (NAD+) activity / Fructose catabolism / aldehyde metabolic process / Ethanol oxidation / RA biosynthesis pathway / glyceraldehyde-3-phosphate dehydrogenase (NAD+) (non-phosphorylating) activity / aldehyde dehydrogenase (NAD+) / cellular detoxification of aldehyde / androgen binding / aldehyde dehydrogenase (NAD+) activity / retinal dehydrogenase activity / retinol metabolic process / negative regulation of cold-induced thermogenesis / retinoid metabolic process / GTPase activator activity / NAD binding / axon / synapse / extracellular exosome / 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
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Chem-VMA / YTTERBIUM (III) ION / Aldehyde dehydrogenase 1A1 / Aldehyde dehydrogenase 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsHurley, T.D. / Buchman, C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214567 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy.
Authors: Huddle, B.C. / Grimley, E. / Chtcherbinine, M. / Buchman, C.D. / Takahashi, C. / Debnath, B. / McGonigal, S.C. / Mao, S. / Li, S. / Felton, J. / Pan, S. / Wen, B. / Sun, D. / Neamati, N. / ...Authors: Huddle, B.C. / Grimley, E. / Chtcherbinine, M. / Buchman, C.D. / Takahashi, C. / Debnath, B. / McGonigal, S.C. / Mao, S. / Li, S. / Felton, J. / Pan, S. / Wen, B. / Sun, D. / Neamati, N. / Buckanovich, R.J. / Hurley, T.D. / Larsen, S.D.
History
DepositionAug 26, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,3417
Polymers54,8981
Non-polymers1,4446
Water5,206289
1
A: Retinal dehydrogenase 1
hetero molecules

A: Retinal dehydrogenase 1
hetero molecules

A: Retinal dehydrogenase 1
hetero molecules

A: Retinal dehydrogenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,36628
Polymers219,5904
Non-polymers5,77524
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
crystal symmetry operation5_655-x+1,y,-z1
crystal symmetry operation6_555x,-y,-z1
Buried area28230 Å2
ΔGint-232 kcal/mol
Surface area58050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.032, 109.032, 82.888
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number89
Space group name H-MP422
Components on special symmetry positions
IDModelComponents
11A-979-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Retinal dehydrogenase 1 / RalDH1 / ALDH-E1 / ALHDII / Aldehyde dehydrogenase family 1 member A1 / Aldehyde dehydrogenase / cytosolic


Mass: 54897.590 Da / Num. of mol.: 1 / Mutation: N121S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH1A1, ALDC, ALDH1, PUMB1 / Plasmid: pET7b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: V9HW83, UniProt: P00352*PLUS

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Non-polymers , 5 types, 295 molecules

#2: Chemical ChemComp-YB / YTTERBIUM (III) ION


Mass: 173.040 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Yb
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#5: Chemical ChemComp-VMA / 1-methyl-5-phenyl-6-{[(1R)-1-(pyridin-2-yl)ethyl]sulfanyl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 363.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17N5OS / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 289 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.24 Å3/Da / Density % sol: 45.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.4
Details: 100 mM sodium BisTris, pH 6.4, 9% PEG3350, 200 mM NaCl, and 5-10 mM YbCl3, 250 uM 1-methyl-5-phenyl-6-((1-(pyridin-2-yl)ethyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one and 1% v/v DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Mar 20, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.9→109.03 Å / Num. obs: 39319 / % possible obs: 98.4 % / Redundancy: 9.5 % / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.036 / Rrim(I) all: 0.112 / Χ2: 1.052 / Net I/σ(I): 7.7
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.9390.77619150.9520.2670.8211.04797.5
1.93-1.979.20.69919140.9480.2390.741.04797.7
1.97-2.019.40.59519060.9660.2020.6291.06197.9
2.01-2.059.50.50419400.9750.170.5321.08298.2
2.05-2.099.50.45419270.9770.1530.481.0998.1
2.09-2.149.60.41119410.9820.1380.4331.09797.9
2.14-2.199.60.37518920.9820.1260.3961.10298.2
2.19-2.259.70.32519400.990.1090.3431.09898
2.25-2.329.70.2719590.9910.0910.2851.08698.3
2.32-2.399.70.24819330.9920.0830.2621.08498.6
2.39-2.489.60.24119810.9910.0810.2541.08499
2.48-2.589.70.19419520.9940.0650.2051.06798.7
2.58-2.79.60.15519590.9960.0520.1641.0698.8
2.7-2.849.60.13719800.9960.0460.1441.05699.3
2.84-3.029.60.10719800.9970.0360.1130.96199
3.02-3.259.50.08719920.9980.030.0920.97599.2
3.25-3.589.50.06920100.9980.0230.0730.96699.4
3.58-4.099.40.05620230.9990.0190.060.97899.6
4.09-5.169.20.04320610.9980.0150.0461.06699.2
5.16-508.60.05121140.9980.0180.0551.0496

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
REFMAC5.8.0155refinement
PDB_EXTRACT3.25data extraction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DUM
Resolution: 1.9→109.03 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.935 / SU B: 13.127 / SU ML: 0.185 / SU R Cruickshank DPI: 0.1826 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.183 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2625 1974 5.1 %RANDOM
Rwork0.2045 ---
obs0.2074 36888 97.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.65 Å2 / Biso mean: 40.803 Å2 / Biso min: 23.17 Å2
Baniso -1Baniso -2Baniso -3
1--2.31 Å20 Å20 Å2
2---2.31 Å20 Å2
3---4.62 Å2
Refinement stepCycle: final / Resolution: 1.9→109.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3814 0 74 289 4177
Biso mean--46.22 41.21 -
Num. residues----494
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194003
X-RAY DIFFRACTIONr_bond_other_d0.0020.023804
X-RAY DIFFRACTIONr_angle_refined_deg1.3681.9835436
X-RAY DIFFRACTIONr_angle_other_deg0.90138786
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2915501
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.99324.731167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.34215677
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.1011517
X-RAY DIFFRACTIONr_chiral_restr0.0730.2598
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214521
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02894
LS refinement shellResolution: 1.9→1.95 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.403 160 4.9 %
Rwork0.339 2670 -
obs--97.45 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
11.32860.4297-0.43930.8741-0.39691.245-0.1252-0.141-0.09280.0944-0.04570.1430.1633-0.00540.17090.08160.0210.1090.03250.02690.528454.091-22.23221.091
20.79410.2726-0.32591.5122-0.96471.3048-0.1286-0.082-0.12050.1480.12130.26510.0125-0.19390.00730.05990.02350.08320.0822-0.01980.55628.213-10.31521.178
30.3248-0.4181-0.18780.7949-0.23360.9954-0.0631-0.02890.00120.1040.0042-0.0617-0.02690.06420.0590.0169-0.002-0.02820.01490.0420.459669.2113.144.893
400000000000000-00.17910.01550.1390.15990.13010.704430.408-29.68239.655
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 140
2X-RAY DIFFRACTION1A163 - 269
3X-RAY DIFFRACTION2A270 - 485
4X-RAY DIFFRACTION3A141 - 162
5X-RAY DIFFRACTION3A486 - 501
6X-RAY DIFFRACTION4A601

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