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- PDB-4dbw: Crystal structure of human 17beta-hydroxysteroid dehydrogenase ty... -

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Basic information

Entry
Database: PDB / ID: 4dbw
TitleCrystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 2'-desmethyl-indomethacin
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / castrate resistant prostate cancer / AKR1C3 selective inhibitor / TIM Barrel / steroid metabolism / 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 / regulation of testosterone biosynthetic process / negative regulation of retinoic acid biosynthetic process / 3beta(or 20alpha)-hydroxysteroid dehydrogenase ...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 / regulation of testosterone biosynthetic process / negative regulation of retinoic acid biosynthetic process / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) / 5alpha-androstane-3beta,17beta-diol dehydrogenase activity / cellular response to prostaglandin D stimulus / delta4-3-oxosteroid 5beta-reductase activity / farnesol catabolic process / macromolecule metabolic process / geranylgeranyl reductase activity / 3alpha-hydroxysteroid 3-dehydrogenase / phenanthrene 9,10-monooxygenase activity / 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 / retinal metabolic process / regulation of retinoic acid receptor signaling pathway / ketosteroid monooxygenase activity / steroid dehydrogenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / testosterone 17-beta-dehydrogenase (NADP+) activity / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / 17-beta-hydroxysteroid dehydrogenase (NAD+) activity / NAD-retinol dehydrogenase activity / aldo-keto reductase (NADP) activity / cyclooxygenase pathway / positive regulation of endothelial cell apoptotic process / prostaglandin H2 endoperoxidase reductase activity / NADP-retinol dehydrogenase activity / Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor / daunorubicin metabolic process / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / doxorubicin metabolic process / retinal dehydrogenase activity / bile acid binding / prostaglandin metabolic process / retinoid metabolic process / alditol:NADP+ 1-oxidoreductase activity / renal absorption / steroid metabolic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Retinoid metabolism and transport / keratinocyte differentiation / cellular response to calcium ion / cellular response to starvation / response to nutrient / positive regulation of cell death / cellular response to cadmium ion / cellular response to reactive oxygen species / male gonad development / positive regulation of reactive oxygen species metabolic process / positive regulation of protein kinase B signaling / 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. / Aldo/keto reductase family signature 2. / Aldo/keto reductase, conserved site / NADP-dependent oxidoreductase domain / 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. / Aldo/keto reductase family signature 2. / Aldo/keto reductase, conserved site / NADP-dependent oxidoreductase domain / 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-511 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member C3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.802 Å
AuthorsChen, M. / Christianson, D.W. / Marnett, L.J. / Penning, T.M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17 beta-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.
Authors: Liedtke, A.J. / Adeniji, A.O. / Chen, M. / Byrns, M.C. / Jin, Y. / Christianson, D.W. / Marnett, L.J. / Penning, T.M.
History
DepositionJan 16, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2013Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version

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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)76,6548
Polymers73,7922
Non-polymers2,8626
Water10,845602
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3274
Polymers36,8961
Non-polymers1,4313
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,3274
Polymers36,8961
Non-polymers1,4313
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.346, 49.089, 83.445
Angle α, β, γ (deg.)74.300, 87.040, 69.950
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 / 3-alpha- ...17-beta-hydroxysteroid dehydrogenase type 5 / 17-beta-HSD 5 / 3-alpha-HSD type II / 3-alpha-hydroxysteroid dehydrogenase type 2 / 3-alpha-HSD type 2 / Chlordecone reductase homolog HAKRb / Dihydrodiol dehydrogenase 3 / DD-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: 36896.215 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS / Plasmid: PET16B / Production host: Escherichia coli (E. coli) / Strain (production host): C41(DE3)
References: UniProt: P42330, EC: 1.1.1.213, indanol dehydrogenase, prostaglandin-F synthase, EC: 1.1.1.63, testosterone 17beta-dehydrogenase (NADP+), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
#2: 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
#3: Chemical
ChemComp-511 / [1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid / 2'-desmethyl-indomethacin


Mass: 343.761 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H14ClNO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 602 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsH5Q IS A NATURAL VARIANT.

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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: 2.37 Å3/Da / Density % sol: 48.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 15% PEG8000, 0.1 M MES, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 22, 2010
RadiationMonochromator: sagitally focused Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. all: 62653 / Num. obs: 60585 / % possible obs: 96.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 2.9 % / Biso Wilson estimate: 28.1 Å2 / Rmerge(I) obs: 0.05 / Χ2: 1.015 / Net I/σ(I): 11.2
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.8-1.862.70.28256070.978189.8
1.86-1.942.80.23359171.022194.7
1.94-2.032.90.17760761.012196.6
2.03-2.132.90.13361060.993196.9
2.13-2.272.90.10561020.981197.9
2.27-2.442.90.0861011.029197.1
2.44-2.692.90.06161241.031198.5
2.69-3.082.90.04761861.046198.1
3.08-3.882.90.03461700.959198.8
3.88-502.90.02861961.089198.8

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.5_2refinement
PDB_EXTRACT3.1data extraction
HKL-2000data collection
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1S2A
Resolution: 1.802→35.057 Å / Occupancy max: 1 / Occupancy min: 0.33 / FOM work R set: 0.8003 / SU ML: 0.24 / Isotropic thermal model: ISOTROPIC / Cross valid method: THROUGHOUT / σ(F): 0.09 / Phase error: 26.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2346 2893 5.08 %RANDOM
Rwork0.1783 ---
all0.194 60585 --
obs0.1811 56940 90.78 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.87 Å2 / ksol: 0.317 e/Å3
Displacement parametersBiso max: 81.6 Å2 / Biso mean: 28.4614 Å2 / Biso min: 11.67 Å2
Baniso -1Baniso -2Baniso -3
1-15.7525 Å2-8.3012 Å2-7.9946 Å2
2---5.6697 Å22.2563 Å2
3----10.0827 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.29 Å0.23 Å
Luzzati d res low-50 Å
Luzzati sigma a0.35 Å0.37 Å
Refinement stepCycle: LAST / Resolution: 1.802→35.057 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5078 0 192 602 5872
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0045431
X-RAY DIFFRACTIONf_angle_d0.917383
X-RAY DIFFRACTIONf_chiral_restr0.062787
X-RAY DIFFRACTIONf_plane_restr0.004943
X-RAY DIFFRACTIONf_dihedral_angle_d19.6982117
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 21

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.802-1.83120.27781190.23652023214272
1.8312-1.86280.31991090.2192163227277
1.8628-1.89670.25791460.22242308245481
1.8967-1.93320.26231230.21062273239681
1.9332-1.97260.28351180.21492459257785
1.9726-2.01550.25561360.20292419255587
2.0155-2.06240.29341390.20422562270189
2.0624-2.1140.25271550.1952512266790
2.114-2.17110.26021270.19372609273692
2.1711-2.2350.2681450.19282545269089
2.235-2.30710.27891470.20442620276793
2.3071-2.38960.24531500.18312695284595
2.3896-2.48520.2751280.18662664279294
2.4852-2.59830.23481360.18462701283795
2.5983-2.73520.24411520.18352748290096
2.7352-2.90650.23411440.18172764290897
2.9065-3.13080.21911500.19262750290098
3.1308-3.44560.24191330.18412834296799
3.4456-3.94360.20831450.16092810295598
3.9436-4.96630.19261440.13332800294499
4.9663-35.06340.161470.13582788293599

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