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- PDB-8b3n: Human Aldose Reductase Mutant A299G/L300G in Complex with a Ligan... -

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Basic information

Entry
Database: PDB / ID: 8b3n
TitleHuman Aldose Reductase Mutant A299G/L300G 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 / mutant A299G/L300G / SAR_061 ligand / nadp+ / diabetes / ligand in 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 / retinoid metabolic process / renal water homeostasis / 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: 1.03 Å
AuthorsHubert, L.-S. / Heine, A. / Klebe, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Human Aldose Reductase Mutant A299G/L300G in Complex with a Ligand with an IDD Structure (3-({[2-(carboxymethoxy)-4-fluorobenzoyl]amino}methyl)benzoic acid)
Authors: Hubert, L.-S. / Heine, A. / Klebe, G.
History
DepositionSep 16, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: 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)37,1114
Polymers35,8281
Non-polymers1,2833
Water7,782432
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1500 Å2
ΔGint-5 kcal/mol
Surface area12720 Å2
Unit cell
Length a, b, c (Å)47.272, 66.721, 49.358
Angle α, β, γ (deg.)90.000, 92.134, 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: 35828.207 Da / Num. of mol.: 1 / Mutation: A299G, L300G
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-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
#4: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 432 / 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: 43.35 %
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+, 10% (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+, 10% (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 with ligand

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.82656 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 2, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.82656 Å / Relative weight: 1
ReflectionResolution: 1.03→39.7 Å / Num. obs: 143107 / % possible obs: 94.5 % / Redundancy: 3.4 % / Biso Wilson estimate: 7.49 Å2 / CC1/2: 0.998 / Rsym value: 0.06 / Net I/σ(I): 12
Reflection shellResolution: 1.03→1.09 Å / Mean I/σ(I) obs: 2.4 / Num. unique obs: 22347 / CC1/2: 0.81 / Rsym value: 0.47 / % possible all: 91.7

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
Cootmodel building
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4PRR

4prr


Resolution: 1.03→38.55 Å / SU ML: 0.0736 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 14.4009
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1543 4282 2.99 %
Rwork0.1355 138697 -
obs0.136 142979 94.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 11.76 Å2
Refinement stepCycle: LAST / Resolution: 1.03→38.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2466 0 86 432 2984
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062795
X-RAY DIFFRACTIONf_angle_d0.97033840
X-RAY DIFFRACTIONf_chiral_restr0.0785420
X-RAY DIFFRACTIONf_plane_restr0.0077534
X-RAY DIFFRACTIONf_dihedral_angle_d16.38321071
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.03-1.040.21191300.21014226X-RAY DIFFRACTION87.61
1.04-1.050.23121410.19834548X-RAY DIFFRACTION92.94
1.05-1.070.19541400.18834540X-RAY DIFFRACTION93.69
1.07-1.080.21031410.1854556X-RAY DIFFRACTION92.9
1.08-1.090.20041380.18414445X-RAY DIFFRACTION90.81
1.09-1.110.19421390.17044518X-RAY DIFFRACTION93.08
1.11-1.120.18121430.15654638X-RAY DIFFRACTION94.06
1.12-1.140.18531410.14714553X-RAY DIFFRACTION94.37
1.14-1.160.16761420.14034612X-RAY DIFFRACTION94.1
1.16-1.180.1681430.13624610X-RAY DIFFRACTION93.97
1.18-1.20.14681410.13184612X-RAY DIFFRACTION94.57
1.2-1.220.1411450.13074676X-RAY DIFFRACTION95.28
1.22-1.240.16121430.12844633X-RAY DIFFRACTION95.18
1.24-1.270.16661430.12514621X-RAY DIFFRACTION94.69
1.27-1.30.13831450.12474679X-RAY DIFFRACTION95.26
1.3-1.330.13781350.13074439X-RAY DIFFRACTION92.09
1.33-1.360.15741420.12444651X-RAY DIFFRACTION94.56
1.36-1.40.15511460.12244721X-RAY DIFFRACTION96.22
1.4-1.440.15881460.12114715X-RAY DIFFRACTION96.43
1.44-1.480.13261470.11674742X-RAY DIFFRACTION96.35
1.48-1.540.13431440.11894673X-RAY DIFFRACTION95.84
1.54-1.60.13821460.11944687X-RAY DIFFRACTION95.78
1.6-1.670.15021450.12254699X-RAY DIFFRACTION96.21
1.67-1.760.16351440.13264668X-RAY DIFFRACTION94.93
1.76-1.870.15171380.13194510X-RAY DIFFRACTION92.04
1.87-2.010.13351460.13014724X-RAY DIFFRACTION96.26
2.01-2.220.14931470.12144746X-RAY DIFFRACTION96.43
2.22-2.540.13781470.12954763X-RAY DIFFRACTION96.46
2.54-3.20.14971440.14014684X-RAY DIFFRACTION94.67
3.2-38.550.15661500.14134808X-RAY DIFFRACTION96.01

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