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

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Basic information

Entry
Database: PDB / ID: 7jwt
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
Chem-VM4 / YTTERBIUM (III) ION / Aldehyde dehydrogenase 1A1 / Aldehyde dehydrogenase 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 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)55,4854
Polymers54,8981
Non-polymers5873
Water6,972387
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)221,93816
Polymers219,5904
Non-polymers2,34812
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 area21870 Å2
ΔGint-134 kcal/mol
Surface area59790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.205, 109.205, 83.219
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-998-

HOH

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Components

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


Mass: 173.040 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Yb
#3: Chemical ChemComp-VM4 / 6-{[(1R)-1-(3-hydroxyphenyl)ethyl]sulfanyl}-1-methyl-5-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 378.448 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18N4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 387 / 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: 2.26 Å3/Da / Density % sol: 45.57 %
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 6-((1-(3-hydroxyphenyl)ethyl)thio)-1-methyl-5-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 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: 1.8→109.21 Å / Num. obs: 46913 / % possible obs: 99.5 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.046 / Rrim(I) all: 0.121 / Χ2: 1.024 / Net I/av σ(I): 15.4 / Net I/σ(I): 8.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.8-1.836.90.591423120.7990.240.6391.026100
1.83-1.866.90.55523080.8070.2250.61.058100
1.86-1.96.90.48123090.8810.1950.521.074100
1.9-1.946.90.40823320.8970.1650.4411.089100
1.94-1.986.90.38323290.9010.1550.4131.075100
1.98-2.036.90.32323190.9260.1310.3491.097100
2.03-2.086.90.28523270.9320.1160.3081.094100
2.08-2.136.90.25623130.9460.1040.2771.097100
2.13-2.26.90.22423300.9610.0910.2421.052100
2.2-2.276.90.19923340.9690.0810.2151.014100
2.27-2.356.90.18223350.9740.0740.1971.04699.9
2.35-2.446.90.16623490.980.0670.181.02599.9
2.44-2.556.90.15323340.9780.0620.1650.95899.7
2.55-2.696.90.13123540.9860.0530.1420.98399.7
2.69-2.866.90.11823530.9870.0480.1280.96699.8
2.86-3.086.90.09823530.9920.040.1061.03599.5
3.08-3.396.90.08223630.9930.0340.0890.93499.3
3.39-3.886.80.06323730.9960.0260.0680.9499
3.88-4.886.70.04924130.9980.020.0531.01698.6
4.88-506.30.0524730.9980.0210.0550.9195.7

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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

6dum


Resolution: 1.8→109.21 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.917 / SU B: 8.151 / SU ML: 0.13 / SU R Cruickshank DPI: 0.156 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.156 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2534 2386 5.1 %RANDOM
Rwork0.2155 ---
obs0.2174 44527 99.51 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.58 Å2 / Biso mean: 29.3 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å2-0 Å2
2--0.5 Å2-0 Å2
3----0.99 Å2
Refinement stepCycle: final / Resolution: 1.8→109.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3814 0 29 387 4230
Biso mean--30.76 30.58 -
Num. residues----494
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193970
X-RAY DIFFRACTIONr_bond_other_d0.0020.023790
X-RAY DIFFRACTIONr_angle_refined_deg1.2911.975385
X-RAY DIFFRACTIONr_angle_other_deg0.90238754
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1355503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.31424.824170
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.20715680
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6571517
X-RAY DIFFRACTIONr_chiral_restr0.0730.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214520
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02884
LS refinement shellResolution: 1.801→1.847 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.377 193 5 %
Rwork0.329 3246 -
obs--100 %
Refinement TLS params.

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)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.1632-0.331-0.95112.1796-0.46990.9545-0.3771-0.4752-0.74020.55350.1530.00210.12370.15910.22410.28750.13680.12360.14660.21340.364857.5589-27.178523.9086
21.14980.2387-0.23461.6338-0.18670.363-0.1803-0.2552-0.280.37790.04960.11790.03380.0210.13070.14210.06690.10540.06990.07850.140154.1934-16.794717.5401
31.78970.3298-0.55081.402-0.3860.4311-0.2396-0.3624-0.20320.3530.11470.44520.00430.00170.12490.18350.08910.19750.12460.04280.329931.4689-9.241719.9436
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 87
2X-RAY DIFFRACTION2A88 - 269
3X-RAY DIFFRACTION3A270 - 501

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