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- PDB-6tgw: Crystal structure of human Aldehyde dehydrogenase 1A3 in complex ... -

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Basic information

Entry
Database: PDB / ID: 6tgw
TitleCrystal structure of human Aldehyde dehydrogenase 1A3 in complex with a selective inhibitor
ComponentsAldehyde dehydrogenase family 1 member A3
KeywordsOXIDOREDUCTASE / ALDH1A3 / aldehyde dehydrogenase ALDH inhibitor Cancer stem cell / glioblastoma mesenchymal stem cell stem cell
Function / homology
Function and homology information


nucleus accumbens development / optic cup morphogenesis involved in camera-type eye development / olfactory pit development / Harderian gland development / retinoic acid biosynthetic process / embryonic eye morphogenesis / retinal dehydrogenase / embryonic camera-type eye development / aldehyde dehydrogenase [NAD(P)+] activity / RA biosynthesis pathway ...nucleus accumbens development / optic cup morphogenesis involved in camera-type eye development / olfactory pit development / Harderian gland development / retinoic acid biosynthetic process / embryonic eye morphogenesis / retinal dehydrogenase / embryonic camera-type eye development / aldehyde dehydrogenase [NAD(P)+] activity / RA biosynthesis pathway / righting reflex / retinal metabolic process / aldehyde dehydrogenase (NAD+) activity / retinal dehydrogenase activity / retinoic acid metabolic process / retinol metabolic process / inner ear morphogenesis / thyroid hormone binding / face development / neuromuscular process controlling balance / NAD+ binding / locomotory behavior / protein homotetramerization / positive regulation of apoptotic process / apoptotic process / protein homodimerization activity / 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-N98 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Retinaldehyde dehydrogenase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsGaravaglia, S. / Rizzi, M.
CitationJournal: Commun Biol / Year: 2021
Title: A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells.
Authors: Li, J. / Garavaglia, S. / Ye, Z. / Moretti, A. / Belyaeva, O.V. / Beiser, A. / Ibrahim, M. / Wilk, A. / McClellan, S. / Klyuyeva, A.V. / Goggans, K.R. / Kedishvili, N.Y. / Salter, E.A. / ...Authors: Li, J. / Garavaglia, S. / Ye, Z. / Moretti, A. / Belyaeva, O.V. / Beiser, A. / Ibrahim, M. / Wilk, A. / McClellan, S. / Klyuyeva, A.V. / Goggans, K.R. / Kedishvili, N.Y. / Salter, E.A. / Wierzbicki, A. / Migaud, M.E. / Mullett, S.J. / Yates, N.A. / Camacho, C.J. / Rizzi, M. / Sobol, R.W.
History
DepositionNov 18, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2022Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aldehyde dehydrogenase family 1 member A3
B: Aldehyde dehydrogenase family 1 member A3
C: Aldehyde dehydrogenase family 1 member A3
D: Aldehyde dehydrogenase family 1 member A3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,85612
Polymers224,7094
Non-polymers4,1478
Water4,630257
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area22370 Å2
ΔGint-88 kcal/mol
Surface area58400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.030, 158.475, 168.646
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Aldehyde dehydrogenase family 1 member A3 / Aldehyde dehydrogenase 6 / Retinaldehyde dehydrogenase 3 / RalDH3


Mass: 56177.289 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALDH1A3, ALDH6
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P47895, retinal dehydrogenase
#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical
ChemComp-N98 / methyl 5-(1,3-benzodioxol-5-yl)-2-phenyl-pyrazolo[1,5-a]pyrimidine-7-carboxylate


Mass: 373.362 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H15N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 2.41 Å3/Da / Density % sol: 48.95 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: 20% PEG-3350 0.24 M sodium malonate pH 7.0 10 mM TCEP-hydrochloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8729 Å
DetectorType: DECTRIS PILATUS3 X 2M / Detector: PIXEL / Date: Sep 30, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8729 Å / Relative weight: 1
ReflectionResolution: 2.8→47.025 Å / Num. obs: 100894 / % possible obs: 97.8 % / Redundancy: 4.6 % / Rpim(I) all: 0.093 / Rrim(I) all: 0.205 / Rsym value: 0.181 / Net I/av σ(I): 3.9 / Net I/σ(I): 6.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
2.8-2.954.30.6691.13165373280.3530.760.6692.394.2
2.95-3.134.60.4971.53379973760.2550.5620.4973.199.3
3.13-3.354.40.352.13063268990.1830.3970.354.199.1
3.35-3.614.80.2333.23096964230.1170.2620.233699
3.61-3.964.80.1614.52806759080.0810.1820.1617.998.8
3.96-4.434.70.1096.52534453570.0550.1230.10910.398.6
4.43-5.114.50.0877.72110246940.0460.0990.08711.396.9
5.11-6.264.50.1076.61771839800.0560.1220.1079.197
6.26-8.854.50.0778.71433931520.0390.0870.0771197.5
8.85-47.0254.50.05210.3814917970.0270.0590.05214.696.3

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FHZ

5fhz


Resolution: 2.8→47.02 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 0.02 / Phase error: 32.35
RfactorNum. reflection% reflection
Rfree0.2736 5030 4.99 %
Rwork0.201 --
obs0.2046 100894 97.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 96.49 Å2 / Biso mean: 23.3904 Å2 / Biso min: 3.25 Å2
Refinement stepCycle: final / Resolution: 2.8→47.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14765 0 288 257 15310
Biso mean--36.32 16.26 -
Num. residues----1913
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-2.830.3891470.29552665281282
2.83-2.860.38581670.28523160332797
2.86-2.90.31961790.27873222340198
2.9-2.940.37451740.27053163333798
2.94-2.970.31691960.26943256345299
2.98-3.020.35971510.27013276342799
3.02-3.060.35671850.2583206339199
3.06-3.10.31571470.24863283343099
3.1-3.150.3271740.233254342899
3.15-3.20.30231280.22933254338299
3.2-3.260.29381510.23343268341999
3.26-3.320.34321640.22443222338699
3.32-3.380.33491740.22333275344999
3.38-3.450.28971610.22323237339899
3.45-3.530.31441600.20813248340899
3.53-3.610.25891770.20583214339199
3.61-3.70.27251710.19453226339799
3.7-3.80.26321390.17823246338599
3.8-3.910.2362290.17043190341999
3.91-4.040.25591750.17563242341799
4.04-4.180.25352080.17793158336698
4.18-4.350.2521850.16463219340499
4.35-4.550.23381540.15583237339198
4.55-4.790.21691110.14773255336698
4.79-5.090.16741900.15743110330096
5.09-5.480.25721560.17363106326295
5.48-6.030.26121650.18083211337698
6.03-6.90.25551680.19363196336498
6.9-8.680.21241660.16823186335298
8.68-47.020.20881780.17883079325794

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