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- PDB-4wpn: Structure of human ALDH1A1 with inhibitor CM053 -

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Basic information

Entry
Database: PDB / ID: 4wpn
TitleStructure of human ALDH1A1 with inhibitor CM053
ComponentsRetinal dehydrogenase 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / oxidoreductase enzyme inhibitor / 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 / 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 / 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; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde Dehydrogenase; Chain A, domain 1 / 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; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 2 / Aldehyde Dehydrogenase; Chain A, domain 1 / Aldehyde Dehydrogenase; Chain A, domain 1 / 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 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-3ST / YTTERBIUM (III) ION / Aldehyde dehydrogenase 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.95 Å
AuthorsMorgan, C.A. / Hurley, T.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA)R01AA018123 United States
CitationJournal: J.Med.Chem. / Year: 2015
Title: Characterization of Two Distinct Structural Classes of Selective Aldehyde Dehydrogenase 1A1 Inhibitors.
Authors: Morgan, C.A. / Hurley, T.D.
History
DepositionOct 20, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 11, 2015Group: Database references
Revision 1.2Sep 6, 2017Group: Advisory / Author supporting evidence ...Advisory / Author supporting evidence / Database references / Derived calculations / Other / Source and taxonomy / Structure summary
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_assembly_prop / pdbx_struct_oper_list / pdbx_validate_close_contact / struct_keywords
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_assembly_prop.type / _pdbx_struct_assembly_prop.value / _pdbx_struct_oper_list.symmetry_operation / _struct_keywords.text
Revision 1.3Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low / _refine_hist.number_atoms_solvent / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_ligand / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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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)55,7687
Polymers54,9251
Non-polymers8436
Water3,405189
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)223,07028
Polymers219,6984
Non-polymers3,37224
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
crystal symmetry operation5_656-x+1,y,-z+11
crystal symmetry operation6_556x,-y,-z+11
Buried area12570 Å2
ΔGint-76 kcal/mol
Surface area67710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.095, 109.095, 83.256
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-757-

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: 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, retinal dehydrogenase
#2: Chemical ChemComp-3ST / 1-{[1,3-dimethyl-7-(3-methylbutyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]methyl}piperidine-4-carboxamide


Mass: 390.480 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H30N6O3
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-YB / YTTERBIUM (III) ION / Ytterbium


Mass: 173.040 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Yb
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 189 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.26 Å3/Da / Density % sol: 45.46 %
Crystal growTemperature: 298 K / Method: evaporation / pH: 7
Details: PEG3350, sodium chloride, 100mM Bis Tris, ytterbium chloride, sitting drop, Ligand soak overnight
PH range: 6.2-7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-BM / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Mar 12, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 35048 / % possible obs: 99 % / Redundancy: 9.3 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 18.3
Reflection shellResolution: 1.95→1.98 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 3.7 / % possible all: 100

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Processing

SoftwareName: REFMAC / Version: 5.8.0049 / Classification: refinement
RefinementResolution: 1.95→50 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.927 / SU B: 8.986 / SU ML: 0.13 / Cross valid method: THROUGHOUT / ESU R: 0.179 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24301 1837 5 %RANDOM
Rwork0.19428 ---
obs0.19668 35048 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.658 Å2
Baniso -1Baniso -2Baniso -3
1-1.06 Å20 Å2-0 Å2
2--1.06 Å2-0 Å2
3----2.12 Å2
Refinement stepCycle: 1 / Resolution: 1.95→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3785 0 33 189 4007
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0193952
X-RAY DIFFRACTIONr_bond_other_d0.0010.023743
X-RAY DIFFRACTIONr_angle_refined_deg1.2871.9555358
X-RAY DIFFRACTIONr_angle_other_deg0.7462.9888635
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8575503
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.44924.699166
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.90915656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4371517
X-RAY DIFFRACTIONr_chiral_restr0.0740.2589
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214516
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02878
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8131.8882001
X-RAY DIFFRACTIONr_mcbond_other0.8081.8881999
X-RAY DIFFRACTIONr_mcangle_it1.2912.8262507
X-RAY DIFFRACTIONr_mcangle_other1.2922.8262508
X-RAY DIFFRACTIONr_scbond_it1.7352.0581949
X-RAY DIFFRACTIONr_scbond_other1.7342.0591950
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.8143.0272851
X-RAY DIFFRACTIONr_long_range_B_refined4.9116.2694581
X-RAY DIFFRACTIONr_long_range_B_other4.84716.0664531
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.951→2.002 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 132 -
Rwork0.268 2501 -
obs--98.95 %
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)
11.42730.1805-0.41983.6568-0.52331.40570.0947-0.50920.1380.4905-0.28460.7330.0793-0.20110.190.223-0.14610.29930.3448-0.23260.415923.45271.595728.6996
21.05040.0611-0.07311.44650.18780.25940.0854-0.33620.25350.3625-0.22870.32530.0005-0.02140.14330.1029-0.07630.07620.1458-0.14360.201540.813512.786619.339
30.8528-0.0721-0.20061.00710.26040.6940.0562-0.1167-0.17610.0884-0.1449-0.0766-0.02490.07220.08870.0429-0.02490.02330.06760.03130.157256.5651-12.01165.5236
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 62
2X-RAY DIFFRACTION2A63 - 479
3X-RAY DIFFRACTION3A480 - 501

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