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- PDB-6f2u: Potent and selective Aldo-Keto Reductase 1C3 (AKR1C3) inhibitors ... -

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Basic information

Entry
Database: PDB / ID: 6f2u
TitlePotent and selective Aldo-Keto Reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a Bioisosteric Scaffold Hopping Approach to Flufenamic acid
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / aldo-keto reductase 1C3 / AKR1C3 / 17B-HSD5 / Prostate cancer (PCa) / CRPC / bioisosterism / scaffold hopping / inhibitors / X-ray crystallography
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 / macromolecule metabolic process / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 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 / macromolecule metabolic process / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / negative regulation of retinoic acid biosynthetic 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 / : / androsterone dehydrogenase activity / testosterone biosynthetic process / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase activity / RA biosynthesis pathway / testosterone dehydrogenase (NAD+) activity / cellular response to prostaglandin D stimulus / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / ketosteroid monooxygenase activity / 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 / all-trans-retinol dehydrogenase (NAD+) activity / cyclooxygenase pathway / 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 / 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 / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / Retinoid metabolism and transport / keratinocyte differentiation / cellular response to starvation / cellular response to calcium ion / 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-CJ2 / 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: 1.88 Å
AuthorsGoyal, P. / Wahlgren, W.Y. / Friemann, R.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Sweden
CitationJournal: 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
DepositionNov 27, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 4, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 11, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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 / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)73,8946
Polymers71,6222
Non-polymers2,2714
Water3,909217
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2690 Å2
ΔGint-10 kcal/mol
Surface area27350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.046, 53.936, 76.714
Angle α, β, γ (deg.)102.12, 85.42, 103.69
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: 35811.094 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


Mass: 743.405 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C21H28N7O17P3 / Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical ChemComp-CJ2 / 3-[(4-methoxyphenyl)methyl]-5-oxidanyl-~{N}-[3-(trifluoromethyl)phenyl]-1,2,3-triazole-4-carboxamide


Mass: 392.332 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H15F3N4O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / 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: 2.18 Å3/Da / Density % sol: 43.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 100mM MES pH 6.0, 25% PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9677 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.88→46.91 Å / Num. obs: 46796 / % possible obs: 91.9 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.046 / Net I/σ(I): 15.7
Reflection shellResolution: 1.88→1.98 Å

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ry0

1ry0


Resolution: 1.88→39.86 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 31.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2477 2309 4.95 %
Rwork0.1965 --
obs0.199 46656 91.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.88→39.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5036 0 152 217 5405
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0085316
X-RAY DIFFRACTIONf_angle_d0.917218
X-RAY DIFFRACTIONf_dihedral_angle_d7.6593176
X-RAY DIFFRACTIONf_chiral_restr0.053778
X-RAY DIFFRACTIONf_plane_restr0.006918
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.88-1.92090.3991370.41132828X-RAY DIFFRACTION93
1.9209-1.96560.40361460.37432782X-RAY DIFFRACTION92
1.9656-2.01470.39071500.29632792X-RAY DIFFRACTION93
2.0147-2.06920.35611420.25652800X-RAY DIFFRACTION93
2.0692-2.13010.28141420.22582795X-RAY DIFFRACTION92
2.1301-2.19880.27471720.2252748X-RAY DIFFRACTION92
2.1988-2.27740.30421410.2152815X-RAY DIFFRACTION92
2.2774-2.36860.29361470.20122707X-RAY DIFFRACTION91
2.3686-2.47640.30721290.20482743X-RAY DIFFRACTION90
2.4764-2.60690.26931260.21252659X-RAY DIFFRACTION88
2.6069-2.77020.25431270.20442503X-RAY DIFFRACTION83
2.7702-2.9840.22311020.20462300X-RAY DIFFRACTION75
2.984-3.28420.27081480.2012953X-RAY DIFFRACTION98
3.2842-3.75910.21391680.18022987X-RAY DIFFRACTION99
3.7591-4.73490.21291440.1542986X-RAY DIFFRACTION99
4.7349-39.86880.20491880.17222949X-RAY DIFFRACTION99

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