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

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Entry
Database: PDB / ID: 4fal
TitleCrystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 in complex with 3-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)-N-methylbenzamide (80)
ComponentsAldo-keto reductase family 1 member C3
Keywordsoxidoreductase/oxidoreductase inhibitor / aldo-keto reductase / 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 / 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 / 5-alpha-androstane-3-beta,17-beta-diol dehydrogenase (NADP+) activity / Delta4-3-oxosteroid 5beta-reductase activity / farnesol catabolic process / geranylgeranyl reductase activity / 3alpha-hydroxysteroid 3-dehydrogenase / cellular response to jasmonic acid stimulus / 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) / prostanoid biosynthetic process / testosterone dehydrogenase (NADP+) activity / androsterone dehydrogenase [NAD(P)+] activity / ketosteroid monooxygenase activity / regulation of testosterone biosynthetic process / RA biosynthesis pathway / testosterone biosynthetic process / : / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / testosterone dehydrogenase (NAD+) activity / regulation of retinoic acid receptor signaling pathway / cellular response to prostaglandin D stimulus / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / retinal metabolic process / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / estradiol 17-beta-dehydrogenase [NAD(P)+] activity / all-trans-retinol dehydrogenase (NAD+) activity / : / 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 / bile acid binding / daunorubicin metabolic process / doxorubicin metabolic process / retinal dehydrogenase (NAD+) activity / aldose reductase (NADPH) activity / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / prostaglandin metabolic process / renal absorption / steroid metabolic process / positive regulation of endothelial cell apoptotic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / retinoid metabolic process / Retinoid metabolism and transport / keratinocyte differentiation / response to nutrient / cellular response to calcium ion / cellular response to starvation / 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-0T0 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member C3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsTurnbull, A.P. / Jamieson, S.M.F. / Brooke, D.G. / Heinrich, D. / Atwell, G.J. / Silva, S. / Hamilton, E.J. / Rigoreau, L.J.M. / Trivier, E. / Soudy, C. ...Turnbull, A.P. / Jamieson, S.M.F. / Brooke, D.G. / Heinrich, D. / Atwell, G.J. / Silva, S. / Hamilton, E.J. / Rigoreau, L.J.M. / Trivier, E. / Soudy, C. / Samlal, S.S. / Owen, P.J. / Schroeder, E. / Raynham, T. / Flanagan, J.U. / Denny, W.A.
CitationJournal: J.Med.Chem. / Year: 2012
Title: 3-(3,4-Dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids; a New Class of Highly Potent and Selective Inhibitors of the Type 5 17-beta-hydroxysteroid Dehydrogenase AKR1C3
Authors: Jamieson, S.M. / Brooke, D.G. / Heinrich, D. / Atwell, G.J. / Silva, S. / Hamilton, E.J. / Turnbull, A.P. / Rigoreau, L.J. / Trivier, E. / Soudy, C. / Samlal, S.S. / Owen, P.J. / Schroeder, ...Authors: Jamieson, S.M. / Brooke, D.G. / Heinrich, D. / Atwell, G.J. / Silva, S. / Hamilton, E.J. / Turnbull, A.P. / Rigoreau, L.J. / Trivier, E. / Soudy, C. / Samlal, S.S. / Owen, P.J. / Schroeder, E. / Raynham, T. / Flanagan, J.U. / Denny, W.A.
History
DepositionMay 22, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 10, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,2376
Polymers37,9771
Non-polymers1,2605
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.687, 64.703, 96.650
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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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 / 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: 37977.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS / Plasmid: pET21a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 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


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-0T0 / 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)-N-methylbenzamide


Mass: 330.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18N2O3S
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 161 / 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: 2.42 Å3/Da / Density % sol: 49.09 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 25 % (w/v) PEG1500, 0.1M PCTP buffer, pH 8, VAPOR DIFFUSION, SITTING DROP, temperature 289K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54182 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: Apr 20, 2010 / Details: Varimax HF Optics
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54182 Å / Relative weight: 1
ReflectionResolution: 2→18.65 Å / Num. all: 24949 / Num. obs: 24949 / % possible obs: 97.9 % / Redundancy: 3.5 %
Reflection shellResolution: 2→2.07 Å / Redundancy: 2.3 % / Num. unique all: 2378 / % possible all: 95.2

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Processing

Software
NameVersionClassification
StructureStudiodata collection
PHASERphasing
REFMAC5.5.0072refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2FGB

2fgb


Resolution: 2→18.65 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.939 / SU B: 3.657 / SU ML: 0.102 / Cross valid method: THROUGHOUT / ESU R: 0.17 / ESU R Free: 0.153 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22129 1275 5.1 %RANDOM
Rwork0.18155 ---
obs0.18361 23672 97.7 %-
all-23672 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.853 Å2
Baniso -1Baniso -2Baniso -3
1-1.04 Å20 Å20 Å2
2---0.1 Å20 Å2
3----0.94 Å2
Refinement stepCycle: LAST / Resolution: 2→18.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2438 0 83 161 2682
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0222593
X-RAY DIFFRACTIONr_bond_other_d0.0010.021783
X-RAY DIFFRACTIONr_angle_refined_deg1.9152.0043522
X-RAY DIFFRACTIONr_angle_other_deg1.0353.0054290
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4145308
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.65623.879116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.66815434
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6671516
X-RAY DIFFRACTIONr_chiral_restr0.1350.2387
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0212823
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02514
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.061.51540
X-RAY DIFFRACTIONr_mcbond_other0.3051.5608
X-RAY DIFFRACTIONr_mcangle_it1.81122490
X-RAY DIFFRACTIONr_scbond_it2.78331053
X-RAY DIFFRACTIONr_scangle_it4.0344.51030
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 80 -
Rwork0.264 1654 -
obs--94.91 %

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