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- PDB-6s6w: Crystal Structure of human ALDH1A3 in complex with 2,6-diphenylim... -

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Basic information

Entry
Database: PDB / ID: 6s6w
TitleCrystal Structure of human ALDH1A3 in complex with 2,6-diphenylimidazo[1,2-a]pyridine (compound GA11) and NAD+
ComponentsAldehyde dehydrogenase family 1 member A3
KeywordsCYTOSOLIC PROTEIN / ALDH1A3 GA11 Glioma 2 / 6-diphenylimidazo[1 / 2-a]pyridine Retinaldehyde dehydrogenase inhinitor ALDHs
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
2,6-diphenylimidazo[1,2-a]pyridine / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Retinaldehyde dehydrogenase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.25 Å
AuthorsGelardi, E.L.M. / Quattrini, L. / LaMotta, C. / Ferraris, D.M. / Garavaglia, S.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Ministry of EducationFAR_2016 Italy
CitationJournal: J.Med.Chem. / Year: 2020
Title: Imidazo[1,2-a]pyridine Derivatives as Aldehyde Dehydrogenase Inhibitors: Novel Chemotypes to Target Glioblastoma Stem Cells.
Authors: Quattrini, L. / Gelardi, E.L.M. / Coviello, V. / Sartini, S. / Ferraris, D.M. / Mori, M. / Nakano, I. / Garavaglia, S. / La Motta, C.
History
DepositionJul 3, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_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_label_seq_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)109,4097
Polymers107,6272
Non-polymers1,7815
Water19811
1
A: Aldehyde dehydrogenase family 1 member A3
B: Aldehyde dehydrogenase family 1 member A3
hetero molecules

A: Aldehyde dehydrogenase family 1 member A3
B: Aldehyde dehydrogenase family 1 member A3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)218,81814
Polymers215,2554
Non-polymers3,56310
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Buried area23380 Å2
ΔGint-105 kcal/mol
Surface area61370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.557, 89.357, 159.037
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221

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Components

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


Mass: 53813.703 Da / Num. of mol.: 2
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.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-KXT / 2,6-diphenylimidazo[1,2-a]pyridine


Mass: 270.328 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H14N2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 2.73 Å3/Da / Density % sol: 54.95 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / Details: 2.4M NaMalonate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.07227 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 21, 2018 / Details: Rontec Xflash X-ray fluorescence detector
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07227 Å / Relative weight: 1
ReflectionResolution: 3.25→48.017 Å / Num. all: 18877 / Num. obs: 18877 / % possible obs: 99.8 % / Redundancy: 4.7 % / Rpim(I) all: 0.064 / Rrim(I) all: 0.144 / Rsym value: 0.128 / Net I/av σ(I): 5.7 / Net I/σ(I): 9.8 / Num. measured all: 88980
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
3.25-3.434.60.78711243326900.3990.8870.7872.199.7
3.43-3.634.90.4611.71264225570.2250.5160.4613.699.7
3.63-3.884.90.292.61198824560.1420.3240.295.499.8
3.88-4.24.80.1794.21054122160.0890.2010.1798100
4.2-4.64.60.1076.8957821020.0540.120.10711.899.8
4.6-5.144.90.0888.1930419060.0440.0990.08813.9100
5.14-5.934.70.0997.4802816950.050.1110.09912.699.8
5.93-7.274.40.0799.1639914460.0410.0890.07913.599.8
7.27-10.284.60.03617.8530611520.0190.0410.03625.299.8
10.28-48.0174.20.02919.227616570.0160.0330.02926.597.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.48 Å48.02 Å
Translation5.48 Å48.02 Å

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Processing

Software
NameVersionClassification
PHENIXrefinement
XDSOSX_64data reduction
SCALA3.3.22data scaling
PHASER2.8.2phasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FHZ

5fhz


Resolution: 3.25→48 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflection
Rfree0.2564 --
Rwork0.1773 --
obs-18877 99.8 %
Displacement parametersBiso max: 160.89 Å2 / Biso mean: 78.2344 Å2 / Biso min: 33.14 Å2
Refinement stepCycle: LAST / Resolution: 3.25→48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7458 0 121 11 7590

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