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- PDB-8p2r: Human Aldose Reductase Mutant A299G/L300A in Complex with a Ligan... -

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Basic information

Entry
Database: PDB / ID: 8p2r
TitleHuman Aldose Reductase Mutant A299G/L300A in Complex with a Ligand with an IDD Structure (3-({[2-(carboxymethoxy)-4-fluorobenzoyl]amino}methyl)benzoic acid)
ComponentsAldo-keto reductase family 1 member B1
KeywordsOXIDOREDUCTASE / human Aldose Reductase / hAR / Aldo-keto-reductase / ligand / SAR061 / nadp+ / diabetes / mutant A299G/L300A / transient pocket
Function / homology
Function and homology information


glyceraldehyde oxidoreductase activity / Fructose biosynthesis / fructose biosynthetic process / L-glucuronate reductase activity / aldose reductase / D/L-glyceraldehyde reductase / glycerol dehydrogenase (NADP+) activity / C21-steroid hormone biosynthetic process / NADP-retinol dehydrogenase / Pregnenolone biosynthesis ...glyceraldehyde oxidoreductase activity / Fructose biosynthesis / fructose biosynthetic process / L-glucuronate reductase activity / aldose reductase / D/L-glyceraldehyde reductase / glycerol dehydrogenase (NADP+) activity / C21-steroid hormone biosynthetic process / NADP-retinol dehydrogenase / Pregnenolone biosynthesis / allyl-alcohol dehydrogenase / allyl-alcohol dehydrogenase activity / prostaglandin H2 endoperoxidase reductase activity / regulation of urine volume / metanephric collecting duct development / all-trans-retinol dehydrogenase (NADP+) activity / daunorubicin metabolic process / doxorubicin metabolic process / retinal dehydrogenase (NAD+) activity / aldose reductase (NADPH) activity / epithelial cell maturation / cellular hyperosmotic salinity response / renal water homeostasis / retinoid metabolic process / carbohydrate metabolic process / electron transfer activity / negative regulation of apoptotic process / mitochondrion / extracellular space / extracellular exosome / nucleoplasm / cytosol
Similarity search - Function
Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / Aldo/keto reductase family signature 2. / Aldo/keto reductase, conserved site / Aldo-keto reductase / NADP-dependent oxidoreductase domain / Aldo/keto reductase family / NADP-dependent oxidoreductase domain superfamily
Similarity search - Domain/homology
Chem-4G7 / CITRIC ACID / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member B1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.25 Å
AuthorsKlee, L.-S. / Heine, A. / Klebe, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Human Aldose Reductase Mutant A299G/L300A in Complex with a Ligand with an IDD Structure (3-({[2-(carboxymethoxy)-4-fluorobenzoyl]amino}methyl)benzoic acid)
Authors: Klee, L.-S. / Heine, A. / Klebe, G. / Scheer, F.
History
DepositionMay 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Aldo-keto reductase family 1 member B1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1254
Polymers35,8421
Non-polymers1,2833
Water8,233457
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1500 Å2
ΔGint-5 kcal/mol
Surface area13040 Å2
Unit cell
Length a, b, c (Å)47.335, 66.813, 49.298
Angle α, β, γ (deg.)90.000, 92.100, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Aldo-keto reductase family 1 member B1 / Aldehyde reductase / Aldose reductase / AR


Mass: 35842.234 Da / Num. of mol.: 1 / Mutation: A299G/L300A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1B1, ALDR1, ALR2 / Plasmid: pET15b / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P15121, NADP-retinol dehydrogenase, D/L-glyceraldehyde reductase, allyl-alcohol dehydrogenase, aldose reductase
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#4: Chemical ChemComp-4G7 / 3-({[2-(carboxymethoxy)-4-fluorobenzoyl]amino}methyl)benzoic acid


Mass: 347.295 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14FNO6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 457 / 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: 2.17 Å3/Da / Density % sol: 43.41 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5
Details: 50 mM Di-Ammoniumhydrogen citrate pH 5: 15 mg/mL hAR, 5.2 mg/mL DTT, 0.7 mg/mL NADP+, 12% (w/v) PEG 6000; Reservoir: 120 mM Di-Ammoniumhydrogen citrate pH 5, 20% (w/v) PEG 6000; Soaking: 120 ...Details: 50 mM Di-Ammoniumhydrogen citrate pH 5: 15 mg/mL hAR, 5.2 mg/mL DTT, 0.7 mg/mL NADP+, 12% (w/v) PEG 6000; Reservoir: 120 mM Di-Ammoniumhydrogen citrate pH 5, 20% (w/v) PEG 6000; Soaking: 120 mM di-ammonium hydrogen citrate pH 5.0, 25% PEG 6000, saturated ligand

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Jun 28, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.25→49.27 Å / Num. obs: 76528 / % possible obs: 90.2 % / Redundancy: 6.5 % / Biso Wilson estimate: 9.08 Å2 / CC1/2: 0.999 / Rsym value: 0.052 / Net I/σ(I): 21.63
Reflection shellResolution: 1.25→1.33 Å / Redundancy: 4.9 % / Mean I/σ(I) obs: 3.97 / Num. unique obs: 7826 / CC1/2: 0.912 / Rsym value: 0.346 / % possible all: 57.2

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
Cootmodel building
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.25→21.63 Å / SU ML: 0.0713 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 11.7346
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1364 3061 4 %
Rwork0.1068 73448 -
obs0.1079 76509 90.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 13.53 Å2
Refinement stepCycle: LAST / Resolution: 1.25→21.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2495 0 78 457 3030
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00652881
X-RAY DIFFRACTIONf_angle_d0.97843960
X-RAY DIFFRACTIONf_chiral_restr0.0786427
X-RAY DIFFRACTIONf_plane_restr0.0075556
X-RAY DIFFRACTIONf_dihedral_angle_d18.711125
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.25-1.270.1753750.15071778X-RAY DIFFRACTION47.97
1.27-1.290.1737830.14151999X-RAY DIFFRACTION54.33
1.29-1.310.1676950.1312295X-RAY DIFFRACTION62.17
1.31-1.340.16741110.11942651X-RAY DIFFRACTION71.98
1.34-1.360.12651310.11653146X-RAY DIFFRACTION85.27
1.36-1.390.16041380.10423316X-RAY DIFFRACTION89.92
1.39-1.420.14911410.10213389X-RAY DIFFRACTION92.53
1.42-1.450.14581470.09863512X-RAY DIFFRACTION94.74
1.45-1.490.1371500.09173608X-RAY DIFFRACTION97.61
1.49-1.530.10771500.09353606X-RAY DIFFRACTION97.79
1.53-1.570.13441510.08953613X-RAY DIFFRACTION98.12
1.57-1.620.1391510.08793627X-RAY DIFFRACTION98.36
1.62-1.680.12611520.09063650X-RAY DIFFRACTION98.42
1.68-1.750.1431530.09553664X-RAY DIFFRACTION98.76
1.75-1.830.12341520.09713649X-RAY DIFFRACTION98.91
1.83-1.930.14321520.10273656X-RAY DIFFRACTION99.01
1.93-2.050.13141540.10133690X-RAY DIFFRACTION99.23
2.05-2.20.12541520.09923659X-RAY DIFFRACTION99.37
2.2-2.430.13671550.10483700X-RAY DIFFRACTION99.59
2.43-2.780.12081550.11093740X-RAY DIFFRACTION99.77
2.78-3.50.14231550.11253714X-RAY DIFFRACTION99.92
3.5-21.630.14081580.12183786X-RAY DIFFRACTION99.85

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