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Yorodumi- PDB-6f78: Potent and selective Aldo-Keto Reductase 1C3 (AKR1C3) inhibitors ... -
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-Basic information
Entry | Database: PDB / ID: 6f78 | ||||||
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Title | Potent and selective Aldo-Keto Reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: Application of a Bioisosteric Scaffold Hopping Approach to Flufenamic acid | ||||||
Components | Aldo-keto reductase family 1 member C3 | ||||||
Keywords | OXIDOREDUCTASE / 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 / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / 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 / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / negative regulation of retinoic acid biosynthetic process / macromolecule metabolic process / 5alpha-androstane-3beta,17beta-diol dehydrogenase activity / Delta4-3-oxosteroid 5beta-reductase activity / 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) / farnesol catabolic process / geranylgeranyl reductase activity / 3alpha-hydroxysteroid 3-dehydrogenase / : / cellular response to jasmonic acid stimulus / regulation of testosterone biosynthetic process / dihydrotestosterone 17-beta-dehydrogenase activity / androsterone dehydrogenase activity / testosterone biosynthetic process / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase activity / testosterone dehydrogenase (NAD+) activity / RA biosynthesis pathway / cellular response to prostaglandin D stimulus / ketosteroid monooxygenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / regulation of retinoic acid receptor signaling pathway / retinal metabolic process / testosterone 17-beta-dehydrogenase (NADP+) activity / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / estradiol 17-beta-dehydrogenase [NAD(P)+] activity / aldo-keto reductase (NADPH) activity / cyclooxygenase pathway / all-trans-retinol dehydrogenase (NAD+) activity / positive regulation of endothelial cell apoptotic process / prostaglandin H2 endoperoxidase reductase activity / 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 / bile acid binding / retinal dehydrogenase activity / 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 / 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 / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å | ||||||
Authors | Goyal, P. / Wahlgren, W.Y. / Friemann, R. | ||||||
Funding support | Sweden, 1items
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Citation | Journal: Eur J Med Chem / Year: 2018 Title: Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid. Authors: Pippione, A.C. / Carnovale, I.M. / Bonanni, D. / Sini, M. / Goyal, P. / Marini, E. / Pors, K. / Adinolfi, S. / Zonari, D. / Festuccia, C. / Wahlgren, W.Y. / Friemann, R. / Bagnati, R. / ...Authors: Pippione, A.C. / Carnovale, I.M. / Bonanni, D. / Sini, M. / Goyal, P. / Marini, E. / Pors, K. / Adinolfi, S. / Zonari, D. / Festuccia, C. / Wahlgren, W.Y. / Friemann, R. / Bagnati, R. / Boschi, D. / Oliaro-Bosso, S. / Lolli, M.L. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6f78.cif.gz | 285.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6f78.ent.gz | 232.2 KB | Display | PDB format |
PDBx/mmJSON format | 6f78.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/f7/6f78 ftp://data.pdbj.org/pub/pdb/validation_reports/f7/6f78 | HTTPS FTP |
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-Related structure data
Related structure data | 6f2uC 1ry0S S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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2 |
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Unit cell |
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-Components
#1: Protein | Mass: 36305.547 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 | #3: Chemical | #4: Chemical | #5: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.4 Å3/Da / Density % sol: 48.78 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion / Details: 100mM MES pH 6.0, 25% PEG 8000 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 7, 2017 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 1.3→80.11 Å / Num. obs: 156106 / % possible obs: 93.9 % / Redundancy: 7.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.05 / Rrim(I) all: 0.053 / Net I/σ(I): 18.6 |
Reflection shell | Resolution: 1.3→1.37 Å |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 1ry0 Resolution: 1.3→44.37 Å / SU ML: 0.09 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 17.93 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 1.3→44.37 Å
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Refine LS restraints |
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LS refinement shell |
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