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- PDB-4puw: Human Aldose Reductase complexed with a ligand with an IDD struct... -

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Basic information

Entry
Database: PDB / ID: 4puw
TitleHuman Aldose Reductase complexed with a ligand with an IDD structure (2-[5-fluoro-2-(prop-2-ynylcarbamoyl)phenoxy]acetic acid) at 1.12 A
ComponentsAldose reductase
KeywordsOxidoreductase/Oxidoreductase inhibitor / Tim Barrel / Oxidoreductase-Oxidoreductase inhibitor 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 / 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. / 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
Chem-2WQ / 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: 1.12 Å
AuthorsRechlin, C. / Heine, A. / Klebe, G.
CitationJournal: To be Published
Title: Aldose Reductase: How expensive is the opening of the specificity pocket? IDD ligands under investigation
Authors: Rechlin, C. / Heine, A. / Scheer, F. / Toth, P. / Diederich, W. / Klebe, G.
History
DepositionMar 14, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)37,0854
Polymers35,8981
Non-polymers1,1873
Water7,242402
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.411, 66.688, 47.353
Angle α, β, γ (deg.)90.00, 92.02, 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 (E. coli) / Strain (production host): BL21 Gold / References: UniProt: P15121, aldose reductase
#2: Chemical ChemComp-2WQ / [5-fluoro-2-(prop-2-yn-1-ylcarbamoyl)phenoxy]acetic acid


Mass: 251.211 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H10FNO4
#3: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#4: 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 402 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAUTHORS HAVE INDICATED THAT THE SEQUENCING RESULT OF THE PLASMID USED SHOWED A ILE IN POSITION 4. ...AUTHORS HAVE INDICATED THAT THE SEQUENCING RESULT OF THE PLASMID USED SHOWED A ILE IN POSITION 4. THIS SEQUENCE CONFLICT IS ALSO ALREADY REPORTED IN THE UNIPROT ENTRY P15121

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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: 43.37 %
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. 9 microliter of the crystallization ...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. 9 microliter of the crystallization solution were mixed with 3 microliter of a 5 mM solution of the inhibitor in 120 mM di-Ammoniumhydrogen citrate pH 5.0 with 25 % (m/V) PEG 6000 and 5 % DMSO, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.91841 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 18, 2013 / Details: Silicon, active surface 50 nm Rh-coated
RadiationMonochromator: Double Crystal Monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.12→50 Å / Num. all: 117148 / Num. obs: 117148 / % possible obs: 99.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.5 % / Biso Wilson estimate: 7.351 Å2 / Rsym value: 0.059 / Net I/σ(I): 15.99
Reflection shellResolution: 1.12→1.14 Å / Redundancy: 2.3 % / Mean I/σ(I) obs: 2.44 / Num. unique all: 5781 / Rsym value: 0.426 / % possible all: 100

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.4_1496)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2dux

2dux


Resolution: 1.12→18.486 Å / SU ML: 0.07 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 12.74 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.1568 5867 5.01 %random
Rwork0.137 ---
obs0.138 117117 99.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.12→18.486 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2482 0 79 402 2963
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062742
X-RAY DIFFRACTIONf_angle_d1.2643763
X-RAY DIFFRACTIONf_dihedral_angle_d14.4411030
X-RAY DIFFRACTIONf_chiral_restr0.079416
X-RAY DIFFRACTIONf_plane_restr0.007483
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1204-1.13310.20051730.18333659X-RAY DIFFRACTION99
1.1331-1.14640.1881720.17283724X-RAY DIFFRACTION100
1.1464-1.16040.18512150.15953684X-RAY DIFFRACTION100
1.1604-1.17510.18311930.15643706X-RAY DIFFRACTION100
1.1751-1.19050.17542040.15053718X-RAY DIFFRACTION100
1.1905-1.20680.14581890.14763712X-RAY DIFFRACTION100
1.2068-1.22410.16112100.14213681X-RAY DIFFRACTION100
1.2241-1.24230.16011910.13993737X-RAY DIFFRACTION100
1.2423-1.26180.16791950.13553700X-RAY DIFFRACTION100
1.2618-1.28240.15941800.13333727X-RAY DIFFRACTION100
1.2824-1.30450.16022070.12893674X-RAY DIFFRACTION100
1.3045-1.32830.14811970.12993709X-RAY DIFFRACTION100
1.3283-1.35380.16052250.12083736X-RAY DIFFRACTION100
1.3538-1.38140.13121860.12193677X-RAY DIFFRACTION100
1.3814-1.41150.1461970.11713737X-RAY DIFFRACTION100
1.4115-1.44430.14191990.11433716X-RAY DIFFRACTION100
1.4443-1.48040.13392090.11183716X-RAY DIFFRACTION100
1.4804-1.52040.13842000.10833685X-RAY DIFFRACTION100
1.5204-1.56510.12951950.11263733X-RAY DIFFRACTION100
1.5651-1.61560.152070.11133692X-RAY DIFFRACTION100
1.6156-1.67330.13391950.11143726X-RAY DIFFRACTION100
1.6733-1.74020.13861750.12073740X-RAY DIFFRACTION100
1.7402-1.81940.14831850.12943752X-RAY DIFFRACTION100
1.8194-1.91520.15571850.13843718X-RAY DIFFRACTION100
1.9152-2.03510.16092060.13663702X-RAY DIFFRACTION100
2.0351-2.1920.16011860.13553726X-RAY DIFFRACTION99
2.192-2.41210.15731970.14553723X-RAY DIFFRACTION99
2.4121-2.76020.16122270.15583684X-RAY DIFFRACTION99
2.7602-3.47370.17581860.1553689X-RAY DIFFRACTION98
3.4737-18.48890.15571810.13983667X-RAY DIFFRACTION96

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