|Entry||Database: PDB / ID: 4dbw|
|Title||Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 2'-desmethyl-indomethacin|
|Components||Aldo-keto reductase family 1 member C3|
|Keywords||OXIDOREDUCTASE/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 species||Homo sapiens (human)|
|Method||X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.802 Å|
|Authors||Chen, M. / Christianson, D.W. / Marnett, L.J. / Penning, T.M.|
|Citation||Journal: 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.
|Structure viewer||Molecule: |
Downloads & links
A: Aldo-keto reductase family 1 member C3
B: Aldo-keto reductase family 1 member C3
A: Aldo-keto reductase family 1 member C3
B: Aldo-keto reductase family 1 member C3
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: 220.127.116.11, indanol dehydrogenase, prostaglandin-F synthase, EC: 18.104.22.168, testosterone 17beta-dehydrogenase (NADP+), trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
|#2: Chemical||#3: Chemical|
ChemComp-511 / [
|#4: Water|| ChemComp-HOH / ||Sequence details||H5Q IS A NATURAL VARIANT.|
|Experiment||Method: X-RAY DIFFRACTION / Number of used crystals: 1|
|Crystal||Density Matthews: 2.37 Å3/Da / Density % sol: 48.2 %|
|Crystal grow||Temperature: 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
|Diffraction||Mean temperature: 100 K|
|Diffraction source||Source: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 0.9795 Å|
|Detector||Type: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 22, 2010|
|Radiation||Monochromator: sagitally focused Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray|
|Radiation wavelength||Wavelength: 0.9795 Å / Relative weight: 1|
|Reflection||Resolution: 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|
|Refinement||Method 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
|Solvent computation||Shrinkage 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 parameters||Biso max: 81.6 Å2 / Biso mean: 28.4614 Å2 / Biso min: 11.67 Å2|
|Refinement step||Cycle: LAST / Resolution: 1.802→35.057 Å|
|Refine LS restraints|
|LS refinement shell|
Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 21
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