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- PDB-8t0t: Structure of Compound 4 bound to human ALDH1A1 -

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Basic information

Entry
Database: PDB / ID: 8t0t
TitleStructure of Compound 4 bound to human ALDH1A1
ComponentsAldehyde dehydrogenase 1A1
KeywordsOXIDOREDUCTASE/INHIBITOR / Inhibitor Complex / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
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
: / YTTERBIUM (III) ION / Aldehyde dehydrogenase 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsHurley, T.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214567 United States
CitationJournal: Chem.Biol.Interact. / Year: 2024
Title: Development of substituted benzimidazoles as inhibitors of human aldehyde dehydrogenase 1A isoenzymes.
Authors: Takahashi, C. / Chtcherbinine, M. / Huddle, B.C. / Wilson, M.W. / Emmel, T. / Hohlman, R.M. / McGonigal, S. / Buckanovich, R.J. / Larsen, S.D. / Hurley, T.D.
History
DepositionJun 1, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aldehyde dehydrogenase 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6124
Polymers54,9251
Non-polymers6873
Water4,990277
1
A: Aldehyde dehydrogenase 1A1
hetero molecules

A: Aldehyde dehydrogenase 1A1
hetero molecules

A: Aldehyde dehydrogenase 1A1
hetero molecules

A: Aldehyde dehydrogenase 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)222,44716
Polymers219,6984
Non-polymers2,74812
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
MethodPISA
Unit cell
Length a, b, c (Å)109.236, 109.236, 83.245
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number89
Space group name H-MP422
Components on special symmetry positions
IDModelComponents
11A-910-

HOH

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Components

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


Mass: 54924.617 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH1A1, ALDC, ALDH1, PUMB1 / Production host: Escherichia coli (E. coli)
References: UniProt: P00352, Oxidoreductases; Acting on the aldehyde or oxo group of donors; With NAD+ or NADP+ as acceptor, retinal dehydrogenase
#2: Chemical ChemComp-YB / YTTERBIUM (III) ION


Mass: 173.040 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Yb
#3: Chemical ChemComp-Y6E / 1-(4-{6-fluoro-3-[4-(methanesulfonyl)piperazine-1-carbonyl]quinolin-4-yl}phenyl)cyclopropane-1-carbonitrile


Mass: 478.539 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H23FN4O3S / 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.: 277 / 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: 2.25 Å3/Da / Density % sol: 45.5 % / Description: plates
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 6.4
Details: 10% PEG 3350, 100 mM Bis-Tris, 200 mM NaCl, 10 mM YbCl3
PH range: 6.2-6.6

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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 210 / Detector: CCD / Date: Nov 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 51200 / % possible obs: 99.9 % / Redundancy: 9.2 % / Rpim(I) all: 0.025 / Rrim(I) all: 0.075 / Χ2: 1.032 / Net I/σ(I): 15.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
1.75-1.7870.65325200.7870.9390.2640.7061.03199.6
1.78-1.817.50.56825150.8690.9640.2220.611.081100
1.81-1.858.10.49425250.8870.970.1850.5281.085100
1.85-1.898.90.43825260.9350.9830.1550.4651.105100
1.89-1.939.20.35625110.9560.9890.1240.3771.131100
1.93-1.979.30.31325210.9640.9910.1080.3321.125100
1.97-2.029.40.25925280.9760.9940.0890.2741.028100
2.02-2.079.50.21825280.9820.9960.0740.231.019100
2.07-2.149.60.1925440.9850.9960.0640.2011.004100
2.14-2.29.60.16125380.9890.9970.0540.171.008100
2.2-2.289.70.14425400.9930.9980.0480.1520.979100
2.28-2.389.70.12425460.9930.9980.0420.1311.036100
2.38-2.489.70.11225490.9950.9990.0380.1180.993100
2.48-2.619.60.09325570.9960.9990.0310.0980.978100
2.61-2.789.60.08225640.9970.9990.0280.0860.938100
2.78-2.999.60.06625780.99810.0220.070.97100
2.99-3.299.60.05325790.99910.0180.0571.029100
3.29-3.779.50.04226170.99910.0140.0440.995100
3.77-4.759.40.03526490.99910.0120.0371.128100
4.75-508.70.03727650.99910.0130.041.00898.6

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-3000data scaling
HKL-3000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→35.03 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 24.84 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2403 2672 5.23 %random
Rwork0.1984 ---
obs0.2006 51103 99.73 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→35.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3816 0 36 277 4129
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073987
X-RAY DIFFRACTIONf_angle_d0.9435416
X-RAY DIFFRACTIONf_dihedral_angle_d5.905557
X-RAY DIFFRACTIONf_chiral_restr0.058595
X-RAY DIFFRACTIONf_plane_restr0.005700
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.780.33521270.28652532X-RAY DIFFRACTION100
1.78-1.820.35181360.27362517X-RAY DIFFRACTION100
1.82-1.850.26581310.25532520X-RAY DIFFRACTION100
1.85-1.890.32251450.26892502X-RAY DIFFRACTION100
1.89-1.940.30031270.25072520X-RAY DIFFRACTION100
1.94-1.990.26491630.24452509X-RAY DIFFRACTION100
1.99-2.040.29421430.23372486X-RAY DIFFRACTION100
2.04-2.10.2621390.24342533X-RAY DIFFRACTION100
2.1-2.170.26541340.23312516X-RAY DIFFRACTION100
2.17-2.250.24661350.22232539X-RAY DIFFRACTION100
2.25-2.340.23581260.20922548X-RAY DIFFRACTION100
2.34-2.440.27821550.21682509X-RAY DIFFRACTION100
2.44-2.570.29321420.20882535X-RAY DIFFRACTION100
2.57-2.730.27081360.21062554X-RAY DIFFRACTION100
2.73-2.940.2341510.19812541X-RAY DIFFRACTION100
2.94-3.240.23561520.19722567X-RAY DIFFRACTION100
3.24-3.710.2111350.17632612X-RAY DIFFRACTION100
3.71-4.670.17471390.14032636X-RAY DIFFRACTION100
4.67-35.030.20711560.16892755X-RAY DIFFRACTION99
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)
11.3104-0.02530.65171.1105-0.53661.6153-0.1062-0.2109-0.36620.1779-0.03070.25730.3259-0.02520.06430.39790.12820.26310.32750.25110.631654.2782-34.211223.626
20.50380.1302-0.07740.6218-0.27010.3713-0.2299-0.2895-0.31680.26310.00630.07540.05250.02280.06430.28650.07370.17990.22710.11570.328855.4505-18.344218.9563
30.50330.384-0.03290.3128-0.12640.6008-0.2473-0.3004-0.17910.1667-0.01510.32870.0482-0.1101-0.07270.26840.07850.27980.28220.02610.469525.8965-10.893322.5409
41.2501-0.2919-0.29090.46030.12150.3585-0.1939-0.0979-0.05590.10870.0090.01030.04830.01370.1890.16110.0140.00320.12940.01940.156454.0185-2.52299.8085
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 8 through 36 )
2X-RAY DIFFRACTION2chain 'A' and (resid 37 through 269 )
3X-RAY DIFFRACTION3chain 'A' and (resid 270 through 454 )
4X-RAY DIFFRACTION4chain 'A' and (resid 455 through 501 )

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