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

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Basic information

Entry
Database: PDB / ID: 7jwv
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 / gamma-aminobutyric acid biosynthetic process / aminobutyraldehyde dehydrogenase activity / retinal dehydrogenase / aminobutyraldehyde dehydrogenase / Fructose catabolism ...fructosamine catabolic process / 3-deoxyglucosone dehydrogenase activity / benzaldehyde dehydrogenase (NAD+) / benzaldehyde dehydrogenase (NAD+) activity / maintenance of lens transparency / gamma-aminobutyric acid biosynthetic process / aminobutyraldehyde dehydrogenase activity / retinal dehydrogenase / aminobutyraldehyde dehydrogenase / Fructose catabolism / cellular 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 / oxidoreductase activity, acting on the aldehyde or oxo group of donors, NAD or NADP as acceptor / aldehyde dehydrogenase (NAD+) activity / negative regulation of cold-induced thermogenesis / retinal dehydrogenase activity / retinol metabolic process / 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, N-terminal / Aldehyde dehydrogenase, C-terminal / Aldehyde/histidinol dehydrogenase
Similarity search - Domain/homology
Chem-VMJ / YTTERBIUM (III) ION / Aldehyde dehydrogenase 1A1 / Aldehyde dehydrogenase 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 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: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_residues
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)55,4994
Polymers54,8981
Non-polymers6013
Water4,774265
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)221,99416
Polymers219,5904
Non-polymers2,40412
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_585-x,-y+3,z1
crystal symmetry operation5_555-x,y,-z1
crystal symmetry operation6_585x,-y+3,-z1
Buried area21770 Å2
ΔGint-135 kcal/mol
Surface area60110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.194, 109.194, 83.174
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-913-

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 / Ytterbium


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


Mass: 392.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H20N4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


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


Mass: 18.015 Da / Num. of mol.: 265 / 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: 45.53 %
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 5-(4-(hydroxymethyl)phenyl)-1-methyl-6-((1-phenylethyl)thio)-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: 1.6→50 Å / Num. obs: 65962 / % possible obs: 98.9 % / Redundancy: 8.1 % / Rmerge(I) obs: 0.124 / Rpim(I) all: 0.046 / Rrim(I) all: 0.132 / Χ2: 1.035 / Net I/σ(I): 11.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.6-1.6370.62232620.7690.2490.6711.04100
1.63-1.667.80.61633000.7890.2330.661.05199.9
1.66-1.698.10.56532540.8250.2080.6031.10399.8
1.69-1.728.10.51132750.8420.1880.5451.1599.8
1.72-1.768.10.44332990.8730.1630.4721.16699.8
1.76-1.88.10.41132770.8970.1510.4391.17299.8
1.8-1.858.10.36232850.9090.1330.3861.13399.5
1.85-1.98.10.3332850.9220.1210.3521.13899.6
1.9-1.958.20.2932880.9350.1060.3091.11199.6
1.95-2.028.20.26732960.9430.0980.2851.0899.6
2.02-2.098.20.24132710.9510.0880.2571.02199.1
2.09-2.178.20.22432860.960.0820.2380.97999.5
2.17-2.278.20.19733000.9670.0720.210.92798.9
2.27-2.398.20.18232790.9730.0670.1940.91198.9
2.39-2.548.20.16733170.9760.0620.1780.88998.8
2.54-2.748.20.14733020.9780.0540.1570.93798.8
2.74-3.018.20.12432950.9880.0460.1320.92998.1
3.01-3.458.20.09733270.9910.0360.1040.97497.8
3.45-4.348.10.07133320.9960.0260.0760.99897.2
4.34-507.70.05134320.9980.0190.0541.01394.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation7.17 Å30.28 Å
Translation7.17 Å30.28 Å

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASER2.6.1phasing
REFMAC5.8.0155refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6DUM

6dum


Resolution: 1.6→50 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.919 / SU B: 6.546 / SU ML: 0.117 / SU R Cruickshank DPI: 0.1149 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.115 / ESU R Free: 0.114 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2708 3384 5.1 %RANDOM
Rwork0.2347 ---
obs0.2365 62578 98.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 69.66 Å2 / Biso mean: 30.099 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.43 Å2-0 Å2-0 Å2
2--0.43 Å2-0 Å2
3----0.85 Å2
Refinement stepCycle: final / Resolution: 1.6→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3814 0 29 265 4108
Biso mean--24.04 25.5 -
Num. residues----494
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193954
X-RAY DIFFRACTIONr_bond_other_d0.0020.023784
X-RAY DIFFRACTIONr_angle_refined_deg1.3121.975362
X-RAY DIFFRACTIONr_angle_other_deg0.90238738
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1515501
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.64924.699166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.49615676
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7141517
X-RAY DIFFRACTIONr_chiral_restr0.0740.2590
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214488
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02879
LS refinement shellResolution: 1.6→1.642 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.397 269 5 %
Rwork0.359 4563 -
obs--99.79 %
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)
11.7750.02720.24191.9083-0.28220.63470.0301-0.5041-0.12110.4689-0.2346-0.5043-0.02960.08620.20450.1431-0.0892-0.15360.25680.17040.236122.167163.30621.037
22.2284-0.35560.71262.0804-0.32821.16080.0963-0.4166-0.61490.4641-0.2426-0.20210.1071-0.01080.14640.157-0.0827-0.04280.21930.2550.375210.302137.41621.174
31.75430.01850.53741.142-0.03491.12060.0133-0.16050.30950.0498-0.21670.0397-0.0014-0.05050.20340.0089-0.0105-0.01260.0774-0.05030.1165-3.147178.5364.883
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

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