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- PDB-6gxk: Crystal structure of Aldo-Keto Reductase 1C3 (AKR1C3) complexed w... -

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Basic information

Entry
Database: PDB / ID: 6gxk
TitleCrystal structure of Aldo-Keto Reductase 1C3 (AKR1C3) complexed with inhibitor.
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / aldo-keto reductase 1C3 / AKR1C3 / 17betaHSD5 / Prostate cancer / CRPC / bioisosterism / scaffold hopping / inhibitors
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-FFW / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member C3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.7 Å
AuthorsGoyal, P. / Wahlgren, W.Y. / Friemann, R.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Sweden
CitationJournal: Acs Med.Chem.Lett. / Year: 2019
Title: Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3.
Authors: Lolli, M.L. / Carnovale, I.M. / Pippione, A.C. / Wahlgren, W.Y. / Bonanni, D. / Marini, E. / Zonari, D. / Gallicchio, M. / Boscaro, V. / Goyal, P. / Friemann, R. / Rolando, B. / Bagnati, R. ...Authors: Lolli, M.L. / Carnovale, I.M. / Pippione, A.C. / Wahlgren, W.Y. / Bonanni, D. / Marini, E. / Zonari, D. / Gallicchio, M. / Boscaro, V. / Goyal, P. / Friemann, R. / Rolando, B. / Bagnati, R. / Adinolfi, S. / Oliaro-Bosso, S. / Boschi, D.
History
DepositionJun 27, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 8, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2019Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)76,32310
Polymers73,7922
Non-polymers2,5318
Water11,187621
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1625
Polymers36,8961
Non-polymers1,2654
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)38,1625
Polymers36,8961
Non-polymers1,2654
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.308, 49.037, 83.659
Angle α, β, γ (deg.)73.74, 86.74, 70.08
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: 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 / 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-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-FFW / 4-[[1-(4-chlorophenyl)carbonyl-5-methoxy-2-methyl-indol-3-yl]methyl]-1,2,5-oxadiazol-3-one


Mass: 397.812 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H16ClN3O4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 621 / 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: 2.38 Å3/Da / Density % sol: 48.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: 10mM MES pH6.0, 25% PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→80.24 Å / Num. obs: 71030 / % possible obs: 95.2 % / Redundancy: 3.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.034 / Rrim(I) all: 0.065 / Net I/σ(I): 13
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.588 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 10270 / CC1/2: 0.824 / Rpim(I) all: 0.357 / Rrim(I) all: 0.689 / % possible all: 94.2

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
SCALAdata scaling
PHENIXphasing
RefinementResolution: 1.7→44.437 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 22.98
RfactorNum. reflection% reflection
Rfree0.1987 3573 5.03 %
Rwork0.1601 --
obs0.162 71016 95.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.7→44.437 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5202 0 72 621 5895
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065402
X-RAY DIFFRACTIONf_angle_d0.9817328
X-RAY DIFFRACTIONf_dihedral_angle_d8.633218
X-RAY DIFFRACTIONf_chiral_restr0.054786
X-RAY DIFFRACTIONf_plane_restr0.006930
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.72240.35061430.30042520X-RAY DIFFRACTION94
1.7224-1.7460.33631530.27042614X-RAY DIFFRACTION95
1.746-1.77090.28291220.25082530X-RAY DIFFRACTION94
1.7709-1.79730.28311780.23322559X-RAY DIFFRACTION94
1.7973-1.82540.29641210.22282604X-RAY DIFFRACTION94
1.8254-1.85540.2371370.2162516X-RAY DIFFRACTION94
1.8554-1.88740.27041300.20642626X-RAY DIFFRACTION94
1.8874-1.92170.21871430.19692538X-RAY DIFFRACTION95
1.9217-1.95860.23621430.18192615X-RAY DIFFRACTION95
1.9586-1.99860.21051360.1712534X-RAY DIFFRACTION95
1.9986-2.04210.19381360.16612647X-RAY DIFFRACTION95
2.0421-2.08960.1931270.16262563X-RAY DIFFRACTION95
2.0896-2.14180.25981170.16392674X-RAY DIFFRACTION95
2.1418-2.19970.23531460.16962552X-RAY DIFFRACTION95
2.1997-2.26450.19311410.16762569X-RAY DIFFRACTION94
2.2645-2.33750.22461300.17012630X-RAY DIFFRACTION96
2.3375-2.42110.21081280.16792587X-RAY DIFFRACTION96
2.4211-2.5180.21541180.17042691X-RAY DIFFRACTION96
2.518-2.63260.21051490.16042614X-RAY DIFFRACTION96
2.6326-2.77140.20741610.16582575X-RAY DIFFRACTION96
2.7714-2.9450.19481240.16152554X-RAY DIFFRACTION94
2.945-3.17230.21821350.15722655X-RAY DIFFRACTION97
3.1723-3.49140.17131300.14852646X-RAY DIFFRACTION97
3.4914-3.99640.15611410.13492592X-RAY DIFFRACTION96
3.9964-5.03390.14291190.11952637X-RAY DIFFRACTION96
5.0339-44.45220.16721650.13752601X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: -3.5002 Å / Origin y: 17.5158 Å / Origin z: -2.2518 Å
111213212223313233
T0.1791 Å2-0.0053 Å2-0.0276 Å2-0.1317 Å20.0201 Å2--0.1536 Å2
L0.2001 °20.0172 °2-0.0846 °2-0.2715 °20.3638 °2--0.6517 °2
S-0.0179 Å °0.0093 Å °0.0143 Å °-0.0407 Å °0.0022 Å °0.0065 Å °-0.0231 Å °-0.0022 Å °0.0097 Å °
Refinement TLS groupSelection details: all

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