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- PDB-4yvx: Crystal structure of AKR1C3 complexed with glimepiride -

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Basic information

Entry
Database: PDB / ID: 4yvx
TitleCrystal structure of AKR1C3 complexed with glimepiride
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / AKR1C3 inhibitor / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


prostaglandin-F synthase / testosterone 17beta-dehydrogenase (NADP+) / prostaglandin D2 11-ketoreductase activity / ketoreductase activity / prostaglandin-F synthase activity / cellular response to prostaglandin stimulus / cellular response to corticosteroid stimulus / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / negative regulation of retinoic acid biosynthetic process ...prostaglandin-F synthase / testosterone 17beta-dehydrogenase (NADP+) / prostaglandin D2 11-ketoreductase activity / ketoreductase activity / prostaglandin-F synthase activity / cellular response to prostaglandin stimulus / cellular response to corticosteroid stimulus / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / negative regulation of retinoic acid biosynthetic process / 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) / 5alpha-androstane-3beta,17beta-diol dehydrogenase activity / delta4-3-oxosteroid 5beta-reductase activity / farnesol catabolic process / geranylgeranyl reductase activity / 3alpha-hydroxysteroid 3-dehydrogenase / phenanthrene 9,10-monooxygenase activity / macromolecule metabolic process / regulation of testosterone biosynthetic process / cellular response to jasmonic acid stimulus / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase activity / dihydrotestosterone 17-beta-dehydrogenase activity / androsterone dehydrogenase activity / testosterone dehydrogenase (NAD+) activity / testosterone biosynthetic process / RA biosynthesis pathway / regulation of retinoic acid receptor signaling pathway / cellular response to prostaglandin D stimulus / ketosteroid monooxygenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / retinal metabolic process / testosterone 17-beta-dehydrogenase (NADP+) activity / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / estradiol 17-beta-dehydrogenase [NAD(P)] activity / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / aldo-keto reductase (NADPH) activity / cyclooxygenase pathway / all-trans-retinol dehydrogenase (NAD+) activity / prostaglandin H2 endoperoxidase reductase activity / positive regulation of endothelial cell apoptotic process / all-trans-retinol dehydrogenase (NADP+) activity / Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor / daunorubicin metabolic process / doxorubicin metabolic process / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / retinal dehydrogenase activity / bile acid binding / aldose reductase (NADPH) activity / retinoid metabolic process / prostaglandin metabolic process / renal absorption / steroid metabolic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Retinoid metabolism and transport / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / keratinocyte differentiation / cellular response to calcium ion / cellular response to starvation / response to nutrient / male gonad development / positive regulation of reactive oxygen species metabolic process / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G protein-coupled receptor signaling pathway / positive regulation of cell population proliferation / extracellular exosome / nucleus / cytosol / cytoplasm
Similarity search - Function
Aldo-keto reductase family 1 member C / 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 ...Aldo-keto reductase family 1 member C / 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-GMR / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member C3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhao, Y. / Zheng, X. / Zhang, H. / Hu, X.
CitationJournal: Chem.Biol.Interact. / Year: 2015
Title: In vitro inhibition of AKR1Cs by sulphonylureas and the structural basis
Authors: Zhao, Y. / Zheng, X. / Zhang, H. / Zhai, J. / Zhang, L. / Li, C. / Zeng, K. / Chen, Y. / Li, Q. / Hu, X.
History
DepositionMar 20, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Nov 25, 2015Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Structure summary
Revision 1.2Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Aldo-keto reductase family 1 member C3
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,2816
Polymers73,8122
Non-polymers2,4684
Water4,468248
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1403
Polymers36,9061
Non-polymers1,2342
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1230 Å2
ΔGint-5 kcal/mol
Surface area13770 Å2
MethodPISA
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1403
Polymers36,9061
Non-polymers1,2342
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-4 kcal/mol
Surface area13870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.000, 49.265, 83.723
Angle α, β, γ (deg.)74.65, 86.04, 69.41
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Aldo-keto reductase family 1 member C3 / 17-beta-hydroxysteroid dehydrogenase type 5 / 17-beta-HSD 5 / 3-alpha-HSD type II / brain / 3-alpha- ...17-beta-hydroxysteroid dehydrogenase type 5 / 17-beta-HSD 5 / 3-alpha-HSD type II / brain / 3-alpha-hydroxysteroid dehydrogenase type 2 / 3-alpha-HSD type 2 / Chlordecone reductase homolog HAKRb / Dihydrodiol dehydrogenase 3 / DD3 / Dihydrodiol dehydrogenase type I / HA1753 / Indanol dehydrogenase / Prostaglandin F synthase / PGFS / Testosterone 17-beta-dehydrogenase 5 / Trans-1 / 2-dihydrobenzene-1 / 2-diol dehydrogenase


Mass: 36906.230 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1C3 / Production host: Escherichia coli (E. coli)
References: UniProt: P42330, Oxidoreductases, 3alpha-hydroxysteroid 3-dehydrogenase, indanol dehydrogenase, prostaglandin-F synthase, 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+), testosterone ...References: UniProt: P42330, Oxidoreductases, 3alpha-hydroxysteroid 3-dehydrogenase, indanol dehydrogenase, prostaglandin-F synthase, 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+), testosterone 17beta-dehydrogenase (NADP+), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
#2: Chemical ChemComp-GMR / 3-ethyl-4-methyl-N-[2-(4-{[(cis-4-methylcyclohexyl)carbamoyl]sulfamoyl}phenyl)ethyl]-2-oxo-2,5-dihydro-1H-pyrrole-1-car boxamide / glimepiride / Glimepiride


Mass: 490.616 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H34N4O5S / Comment: medication*YM
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 248 / Source method: isolated from a natural source / Formula: H2O

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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: 2.44 Å3/Da / Density % sol: 49.52 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 15-20% (w/v) PEG 8000, 100 mM MES, 0.14M NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION ENHANCE ULTRA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Dec 26, 2014
RadiationMonochromator: multilayer optics / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→80.709 Å / Num. all: 30098 / Num. obs: 30098 / % possible obs: 99.9 % / Redundancy: 5.7 % / Rpim(I) all: 0.071 / Rrim(I) all: 0.171 / Rsym value: 0.155 / Net I/av σ(I): 4.35 / Net I/σ(I): 9.2 / Num. measured all: 171310
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.3-2.425.60.6151.12453643780.2830.6152.5100
2.42-2.575.60.4671.52357341890.2140.4673.2100
2.57-2.755.70.3471.92237239430.1580.3474.3100
2.75-2.975.70.2472.92037935820.1130.2475.8100
2.97-3.255.70.1724.21931533750.0780.1728100
3.25-3.645.80.11561749230390.0520.11511.8100
3.64-4.25.80.0788.71541526720.0350.07817.1100
4.2-5.145.80.05811.21300722530.0260.05821.2100
5.14-7.275.80.0699.71002917250.0310.06915.8100
7.27-25.5055.50.04214.251929420.0190.04232.497.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
SCALA3.3.21data scaling
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4FAM
Resolution: 2.3→80.709 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.908 / SU B: 7.529 / SU ML: 0.175 / Cross valid method: THROUGHOUT / ESU R: 0.388 / ESU R Free: 0.238 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23234 1514 5 %RANDOM
Rwork0.1843 ---
obs0.18671 28584 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.613 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20.04 Å2-0.02 Å2
2--0.03 Å20.05 Å2
3---0.06 Å2
Refinement stepCycle: LAST / Resolution: 2.3→80.709 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5048 0 164 248 5460
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0195340
X-RAY DIFFRACTIONr_bond_other_d0.0020.025096
X-RAY DIFFRACTIONr_angle_refined_deg1.8291.9857250
X-RAY DIFFRACTIONr_angle_other_deg1.047311752
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9125628
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.0224.05242
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.31815920
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4891534
X-RAY DIFFRACTIONr_chiral_restr0.0970.2786
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0216056
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021224
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.0972.5342518
X-RAY DIFFRACTIONr_mcbond_other2.0922.5312517
X-RAY DIFFRACTIONr_mcangle_it3.3713.7893144
X-RAY DIFFRACTIONr_mcangle_other3.3713.7923145
X-RAY DIFFRACTIONr_scbond_it2.4732.8072822
X-RAY DIFFRACTIONr_scbond_other2.4732.8072823
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.0464.1124107
X-RAY DIFFRACTIONr_long_range_B_refined6.71520.9856046
X-RAY DIFFRACTIONr_long_range_B_other6.69420.9425976
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.353 92 -
Rwork0.284 2167 -
obs--100 %

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