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- PDB-4yu1: Human Aldose Reductase complexed with Schl12134 (3-[5-(3-nitrophe... -

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Basic information

Entry
Database: PDB / ID: 4yu1
TitleHuman Aldose Reductase complexed with Schl12134 (3-[5-(3-nitrophenyl)-2-thienyl]propanoic acid) at 1.02 A
ComponentsAldose reductase
KeywordsOXIDOREDUCTASE / Tim-Barrel / Protein-Ligand-Complex
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 / Pregnenolone biosynthesis / NADP-retinol dehydrogenase ...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 / Pregnenolone biosynthesis / NADP-retinol dehydrogenase / allyl-alcohol dehydrogenase / allyl-alcohol dehydrogenase activity / L-ascorbic acid biosynthetic process / metanephric collecting duct development / prostaglandin H2 endoperoxidase reductase activity / regulation of urine volume / all-trans-retinol dehydrogenase (NADP+) activity / daunorubicin metabolic process / doxorubicin metabolic process / retinal dehydrogenase activity / epithelial cell maturation / aldose reductase (NADPH) activity / retinoid metabolic process / cellular hyperosmotic salinity response / renal water homeostasis / carbohydrate metabolic process / electron transfer activity / negative regulation of apoptotic process / extracellular space / extracellular exosome / nucleoplasm / cytosol
Similarity search - Function
Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / NADP-dependent oxidoreductase domain / 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 / TIM Barrel ...Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / NADP-dependent oxidoreductase domain / 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 / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
3-[5-(3-nitrophenyl)thiophen-2-yl]propanoic 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: 1.02 Å
AuthorsRechlin, C. / Heine, A. / Klebe, G.
Funding support1items
OrganizationGrant numberCountry
European Union/ERC268145-DrugProfilBind
CitationJournal: To Be Published
Title: Keys to open the specificity pocket: Biphenylic Inhibitors of the human aldose reductase
Authors: Rechlin, C. / Heine, A. / Ortmann, R. / Schlitzer, M. / Klebe, G.
History
DepositionMar 18, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 23, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aldose reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9193
Polymers35,8981
Non-polymers1,0212
Water7,440413
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-5 kcal/mol
Surface area12940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.449, 66.354, 47.429
Angle α, β, γ (deg.)90.00, 92.31, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 35898.340 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1B1, ALDR1 / Plasmid: pET15B / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Gold / References: UniProt: P15121, 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-53N / 3-[5-(3-nitrophenyl)thiophen-2-yl]propanoic acid


Mass: 277.296 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11NO4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 413 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.15 Å3/Da / Density % sol: 42.9 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 5
Details: Crystallization solution: 50 mM di-Ammoniumhydrogen citrate pH 5.0 PEG6000= 5 % (m/V) DTT= 5.15 g/L NADP+= 0.66 g/L and Human Aldose Reductase= 15 mg/ml.Afterwards the crystals were soaked ...Details: Crystallization solution: 50 mM di-Ammoniumhydrogen citrate pH 5.0 PEG6000= 5 % (m/V) DTT= 5.15 g/L NADP+= 0.66 g/L and Human Aldose Reductase= 15 mg/ml.Afterwards the crystals were soaked into Tris 100 mM 25% (m/V) PEG6000 pH 8.0 saturated with the inhibitor.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.91841 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.02→50 Å / Num. obs: 150587 / % possible obs: 96.7 % / Redundancy: 3.4 % / Rsym value: 0.049 / Net I/σ(I): 14.02
Reflection shellResolution: 1.02→1.08 Å / Redundancy: 3.2 % / Mean I/σ(I) obs: 2.48 / % possible all: 92.9

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.8.4_1492)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2dux

2dux


Resolution: 1.02→24.704 Å / SU ML: 0.07 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 12.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1497 7528 5 %Random selection
Rwork0.1326 ---
obs0.1335 150569 96.72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.02→24.704 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2485 0 67 413 2965
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082803
X-RAY DIFFRACTIONf_angle_d1.3713852
X-RAY DIFFRACTIONf_dihedral_angle_d13.8561054
X-RAY DIFFRACTIONf_chiral_restr0.088428
X-RAY DIFFRACTIONf_plane_restr0.01509
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.0189-1.03050.24082270.23534305X-RAY DIFFRACTION87
1.0305-1.04260.25042390.20954548X-RAY DIFFRACTION94
1.0426-1.05540.21712450.19734652X-RAY DIFFRACTION94
1.0554-1.06870.1922430.18644612X-RAY DIFFRACTION95
1.0687-1.08280.17732480.16734725X-RAY DIFFRACTION95
1.0828-1.09760.16172440.15544621X-RAY DIFFRACTION95
1.0976-1.11330.16482460.1554683X-RAY DIFFRACTION96
1.1133-1.12990.18652480.14024721X-RAY DIFFRACTION95
1.1299-1.14760.13132480.12614706X-RAY DIFFRACTION95
1.1476-1.16640.13832470.12154705X-RAY DIFFRACTION96
1.1664-1.18650.14372500.11874753X-RAY DIFFRACTION96
1.1865-1.20810.12862500.11954739X-RAY DIFFRACTION96
1.2081-1.23130.14972490.11874725X-RAY DIFFRACTION96
1.2313-1.25640.14692510.11534767X-RAY DIFFRACTION97
1.2564-1.28380.13472510.11544780X-RAY DIFFRACTION97
1.2838-1.31360.1342530.11664802X-RAY DIFFRACTION97
1.3136-1.34650.13272510.11324772X-RAY DIFFRACTION98
1.3465-1.38290.13872550.11534837X-RAY DIFFRACTION98
1.3829-1.42360.15342530.11374811X-RAY DIFFRACTION98
1.4236-1.46950.12562550.11644841X-RAY DIFFRACTION98
1.4695-1.5220.14192550.11494851X-RAY DIFFRACTION98
1.522-1.58290.13122560.1124876X-RAY DIFFRACTION99
1.5829-1.6550.13182580.11524891X-RAY DIFFRACTION99
1.655-1.74220.12792550.12334856X-RAY DIFFRACTION99
1.7422-1.85130.12922580.12684902X-RAY DIFFRACTION99
1.8513-1.99420.15472570.13374866X-RAY DIFFRACTION98
1.9942-2.19480.14182560.13134871X-RAY DIFFRACTION98
2.1948-2.51210.14832590.1424915X-RAY DIFFRACTION99
2.5121-3.1640.16352590.14534931X-RAY DIFFRACTION99
3.164-24.71170.15692620.13444977X-RAY DIFFRACTION99

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