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- PDB-6dum: ALDH1A1 N121S in complex with 6-{[(3-fluorophenyl)methyl]sulfanyl... -

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Basic information

Entry
Database: PDB / ID: 6dum
TitleALDH1A1 N121S in complex with 6-{[(3-fluorophenyl)methyl]sulfanyl}-2-(oxetan-3-yl)-5-phenyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (compound 13g)
ComponentsRetinal dehydrogenase 1
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / OXIDOREDUCTASE / 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 / 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; 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-A5Y / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / YTTERBIUM (III) ION / Aldehyde dehydrogenase 1A1 / Aldehyde dehydrogenase 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsBuchman, C.D. / Hurley, T.D.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: J.Med.Chem. / Year: 2018
Title: Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy.
Authors: Huddle, B.C. / Grimley, E. / Buchman, C.D. / Chtcherbinine, M. / Debnath, B. / Mehta, P. / Yang, K. / Morgan, C.A. / Li, S. / Felton, J. / Sun, D. / Mehta, G. / Neamati, N. / Buckanovich, R. ...Authors: Huddle, B.C. / Grimley, E. / Buchman, C.D. / Chtcherbinine, M. / Debnath, B. / Mehta, P. / Yang, K. / Morgan, C.A. / Li, S. / Felton, J. / Sun, D. / Mehta, G. / Neamati, N. / Buckanovich, R.J. / Hurley, T.D. / Larsen, S.D.
History
DepositionJun 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry

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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)56,56612
Polymers54,8981
Non-polymers1,66811
Water3,099172
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)226,26348
Polymers219,5904
Non-polymers6,67344
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 area29950 Å2
ΔGint-363 kcal/mol
Surface area57790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.802, 108.802, 82.877
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-608-

CL

21A-868-

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
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: V9HW83, UniProt: P00352*PLUS, Oxidoreductases; Acting on the aldehyde or oxo group of donors; With NAD+ or NADP+ as acceptor, retinal dehydrogenase

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Non-polymers , 5 types, 183 molecules

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


Mass: 173.040 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Yb
#3: Chemical ChemComp-A5Y / 6-{[(3-fluorophenyl)methyl]sulfanyl}-2-(oxetan-3-yl)-5-phenyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 408.449 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17FN4O2S
#4: Chemical ChemComp-NAI / 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE / NADH / Nicotinamide adenine dinucleotide


Mass: 665.441 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H29N7O14P2
#5: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O

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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: 45.59 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop
Details: 100 mM Bis-Tris, pH 6.2-6.5, 200 mM sodium chloride, 5 mM ytterbium chloride, 6-11% PEG3350
PH range: 6.2-6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 26, 2017
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 33340 / % possible obs: 97.2 % / Redundancy: 12.6 % / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.017 / Rrim(I) all: 0.063 / Χ2: 1.007 / Net I/σ(I): 8.6 / Num. measured all: 418664
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2-2.03120.3160.9870.090.3280.93483.6
2.03-2.0711.90.2940.9910.0840.3060.95886.7
2.07-2.1111.70.260.9920.0750.2710.95289.8
2.11-2.1511.10.2560.9920.0770.2670.93192.1
2.15-2.210.40.2520.9890.0790.2650.96495.8
2.2-2.2512.60.20.9960.0560.2080.98298.3
2.25-2.3113.10.1650.9970.0460.171198.8
2.31-2.3713.20.1550.9970.0430.1611.0399.7
2.37-2.4413.40.1480.9970.0410.1541.018100
2.44-2.5213.30.1370.9980.0380.1421.025100
2.52-2.6113.20.1120.9990.0310.1161.068100
2.61-2.7112.90.1040.9980.030.1091.085100
2.71-2.8411.50.0990.9980.0310.1041.16299.9
2.84-2.9913.50.0750.9990.0210.0781.091100
2.99-3.1713.70.0650.9990.0180.0671.1100
3.17-3.4213.40.0570.9990.0160.0590.997100
3.42-3.76130.0470.9990.0130.0490.937100
3.76-4.3111.70.0440.9990.0130.0460.95599.7
4.31-5.4313.30.0410.0110.0410.98499.9
5.43-5011.80.0450.9990.0130.0470.90399.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
SCALEPACKdata scaling
PDB_EXTRACT3.22data extraction
RefinementResolution: 2→50 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.934 / SU B: 15.824 / SU ML: 0.218 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.205 / ESU R Free: 0.183
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2486 1690 5.1 %RANDOM
Rwork0.1941 ---
obs0.1971 31637 97.15 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 95.15 Å2 / Biso mean: 49.714 Å2 / Biso min: 23.2 Å2
Baniso -1Baniso -2Baniso -3
1--3.38 Å2-0 Å20 Å2
2---3.38 Å20 Å2
3---6.76 Å2
Refinement stepCycle: final / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3814 0 82 172 4068
Biso mean--59.34 46.52 -
Num. residues----494
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193990
X-RAY DIFFRACTIONr_bond_other_d0.0010.023783
X-RAY DIFFRACTIONr_angle_refined_deg1.4731.9855394
X-RAY DIFFRACTIONr_angle_other_deg0.76638735
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3225493
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.81124.727165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.83415672
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8411517
X-RAY DIFFRACTIONr_chiral_restr0.070.2593
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0214472
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02883
LS refinement shellResolution: 1.999→2.051 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 102 -
Rwork0.306 1979 -
all-2081 -
obs--83.95 %
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)
15.00310.66820.52691.0873-0.84452.5855-0.1634-0.1905-0.49760.1206-0.01150.14720.39350.01830.1750.2040.03690.20360.03190.07170.417951.9712-32.119728.2646
21.11610.6998-0.5661.1638-0.44060.6278-0.108-0.0832-0.08190.0513-0.03610.14090.03360.02030.14410.03640.01860.05360.01590.01810.324855.9218-16.877717.3466
30.97870.4779-0.51441.0347-0.67290.8101-0.1275-0.0751-0.07240.10630.08010.26440.0237-0.11440.04730.05830.02240.08830.0551-0.03560.450831.3055-9.314919.9136
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 59
2X-RAY DIFFRACTION2A60 - 271
3X-RAY DIFFRACTION3A272 - 501

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