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- PDB-8rb6: Structure of Aldo-Keto Reductase 1C3 (AKR1C3) in complex with an ... -

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Basic information

Entry
Database: PDB / ID: 8rb6
TitleStructure of Aldo-Keto Reductase 1C3 (AKR1C3) in complex with an inhibitor M689, with the 3-hydroxy-benzoisoxazole moiety. Resolution 2.0A
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / Aldo-keto reductase / AKR1C3 / inhibitor
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 / androsterone dehydrogenase [NAD(P)+] activity / testosterone dehydrogenase (NADP+) activity / regulation of testosterone biosynthetic process / ketosteroid monooxygenase activity / RA biosynthesis pathway / testosterone biosynthetic process / cellular response to prostaglandin D stimulus / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / : / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity / testosterone dehydrogenase (NAD+) activity / regulation of retinoic acid receptor signaling pathway / retinal metabolic process / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / all-trans-retinol dehydrogenase (NAD+) activity / estradiol 17-beta-dehydrogenase [NAD(P)+] 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 / daunorubicin metabolic process / doxorubicin metabolic process / retinal dehydrogenase (NAD+) activity / bile acid binding / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / aldose reductase (NADPH) activity / 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. / 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
Similarity search - Domain/homology
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: 2 Å
AuthorsFrydenvang, K. / Mirza, O.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2024
Title: Structure-guided optimization of 3-hydroxybenzoisoxazole derivatives as inhibitors of Aldo-keto reductase 1C3 (AKR1C3) to target prostate cancer.
Authors: Pippione, A.C. / Kovachka, S. / Vigato, C. / Bertarini, L. / Mannella, I. / Sainas, S. / Rolando, B. / Denasio, E. / Piercy-Mycock, H. / Romalho, L. / Salladini, E. / Adinolfi, S. / Zonari, ...Authors: Pippione, A.C. / Kovachka, S. / Vigato, C. / Bertarini, L. / Mannella, I. / Sainas, S. / Rolando, B. / Denasio, E. / Piercy-Mycock, H. / Romalho, L. / Salladini, E. / Adinolfi, S. / Zonari, D. / Peraldo-Neia, C. / Chiorino, G. / Passoni, A. / Mirza, O.A. / Frydenvang, K. / Pors, K. / Lolli, M.L. / Spyrakis, F. / Oliaro-Bosso, S. / Boschi, D.
History
DepositionDec 3, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 6, 2024Provider: repository / Type: Initial release

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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)76,0608
Polymers73,8122
Non-polymers2,2486
Water4,306239
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0304
Polymers36,9061
Non-polymers1,1243
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0304
Polymers36,9061
Non-polymers1,1243
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.343, 93.191, 83.008
Angle α, β, γ (deg.)90.00, 95.09, 90.00
Int Tables number4
Space group name H-MP1211

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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 / Prostaglandin F synthase / PGFS / Testosterone 17-beta-dehydrogenase 5


Mass: 36906.230 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; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor, 3beta(or 20alpha)-hydroxysteroid dehydrogenase, 3alpha(or 20beta)-hydroxysteroid ...References: UniProt: P42330, Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor, 3beta(or 20alpha)-hydroxysteroid dehydrogenase, 3alpha(or 20beta)-hydroxysteroid dehydrogenase, 17beta-estradiol 17-dehydrogenase, 3alpha-hydroxysteroid 3-dehydrogenase, prostaglandin-F synthase, 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+), testosterone 17beta-dehydrogenase (NADP+)
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-YMC / 4-[[4-(3-hydroxyphenyl)phenyl]amino]-1,2-benzoxazol-3-ol / 4-[(3'-hydroxy[1,1'-biphenyl]-4-yl)amino]-1,2-benzoxazol-3-ol


Mass: 318.326 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H14N2O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 239 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.16 Å3/Da / Density % sol: 43 %
Crystal growTemperature: 279 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.1 M MESH, 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2→61.85 Å / Num. obs: 42384 / % possible obs: 100 % / Redundancy: 7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.041 / Rrim(I) all: 0.108 / Χ2: 0.92 / Net I/σ(I): 9 / Num. measured all: 296998
Reflection shellResolution: 2→2.05 Å / % possible obs: 100 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.602 / Num. measured all: 21558 / Num. unique obs: 3131 / CC1/2: 0.944 / Rpim(I) all: 0.247 / Rrim(I) all: 0.652 / Χ2: 0.87 / Net I/σ(I) obs: 3

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6f2u

6f2u


Resolution: 2→61.85 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 0.42 / Phase error: 26.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2266 2147 5.09 %
Rwork0.1899 --
obs0.1917 42198 99.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→61.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4969 0 152 239 5360
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0035305
X-RAY DIFFRACTIONf_angle_d0.6037206
X-RAY DIFFRACTIONf_dihedral_angle_d13.5992049
X-RAY DIFFRACTIONf_chiral_restr0.044782
X-RAY DIFFRACTIONf_plane_restr0.004918
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.050.31231480.24652674X-RAY DIFFRACTION100
2.05-2.10.27511330.22362642X-RAY DIFFRACTION100
2.1-2.150.26721430.21032692X-RAY DIFFRACTION100
2.15-2.220.24581510.20522625X-RAY DIFFRACTION100
2.22-2.290.24961580.22272660X-RAY DIFFRACTION99
2.29-2.370.25471490.20012650X-RAY DIFFRACTION100
2.37-2.470.26451380.2022656X-RAY DIFFRACTION100
2.47-2.580.23011480.2032686X-RAY DIFFRACTION100
2.58-2.710.23261620.19062613X-RAY DIFFRACTION99
2.71-2.880.20761520.18712652X-RAY DIFFRACTION100
2.88-3.110.22761380.19812699X-RAY DIFFRACTION100
3.11-3.420.24171240.18972699X-RAY DIFFRACTION100
3.42-3.910.19951350.18052675X-RAY DIFFRACTION100
3.91-4.930.18581180.15672708X-RAY DIFFRACTION99
4.93-61.850.22491500.19122720X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.6705-0.40910.0911.62760.83530.4837-0.17590.0987-0.6252-0.02730.34070.06470.9594-0.19570.07450.8656-0.154-0.02640.2587-0.0510.3841-4.6908-33.612635.4902
22.79730.5799-0.11623.0740.75380.81140.10090.1833-0.6913-0.088-0.11750.38730.8811-0.32340.04780.8108-0.238-0.05440.434-0.08230.449-11.5042-34.166228.3149
33.05080.54790.19372.29610.10912.9328-0.02560.5179-0.0365-0.32880.01110.20940.065-0.29940.02410.45360.0116-0.07680.3604-0.00230.2203-5.4877-16.906125.0599
44.2908-1.4006-1.84833.23591.95994.90430.14940.57970.7799-0.6082-0.0541-0.2777-0.9871-0.147-0.02380.64280.0428-0.04370.35070.09780.29-1.2139-1.074522.7166
53.98110.09190.36452.8275-1.00164.14310.00940.10820.50440.0304-0.1150.3164-0.5303-0.59490.12820.42650.0987-0.05760.30650.00650.2495-7.112-4.515131.5933
60.2873-0.2083-0.33918.65523.65491.82220.26410.1855-0.16410.2038-0.5998-0.51650.42260.26560.3490.85790.0812-0.10860.69480.00520.38481.8442-21.707216.8918
71.9555-0.49640.81442.1957-0.53323.086-0.05690.20810.0651-0.40040.05380.0804-0.1414-0.1094-0.00330.2807-0.0234-0.04150.2035-0.01490.208-15.0044-18.101-18.674
83.4959-1.30931.47778.7452-6.88467.83-0.06590.304-0.5171-0.45970.17090.46920.1989-0.4101-0.25420.4413-0.0679-0.10220.2455-0.04840.3502-18.577-34.0465-18.5445
92.04610.22750.74624.3037-0.36655.1957-0.0109-0.0402-0.3047-0.27690.02350.22810.4186-0.2969-0.00050.2113-0.0175-0.03340.16520.01190.243-13.1606-32.2927-10.5419
104.8387-2.5314-0.00867.38521.07023.60130.2199-0.0462-0.81110.0869-0.0362-0.4130.8650.0637-0.20950.26940.0508-0.05280.26030.0150.3843-0.8367-34.1341-5.0539
114.6291-3.5013-0.24287.59321.78893.8054-0.0997-0.49620.1570.33750.108-0.46310.03990.2263-0.05470.2016-0.0102-0.03630.22780.01750.2342-2.8514-18.6001-0.2317
122.7851-2.42580.77027.06130.99323.8724-0.2275-0.5181-0.09680.04560.12640.2537-0.0775-0.35410.18170.1739-0.0209-0.04580.21410.01830.1744-13.5422-15.0207-3.3836
137.20232.7333-2.97544.984-4.23119.0806-0.2203-0.49330.81320.0601-0.19860.2231-0.5576-0.28160.35330.29730.0956-0.11690.2704-0.13540.3879-11.703-1.44611.0644
144.54740.50581.11894.03811.19173.4759-0.31510.27550.6695-0.3629-0.0226-0.0023-0.69780.09170.32470.3134-0.0301-0.06060.2010.0170.2523-9.0254-5.5154-10.8341
156.16441.53791.12025.31251.07564.0472-0.21030.04010.46060.15730.0214-0.8956-0.51040.79940.18150.3747-0.0865-0.12530.3147-0.02940.47011.4866-2.1579-1.184
160.06120.91110.04918.59550.29450.0497-0.0432-0.5854-0.08521.10550.18910.21980.0533-0.4314-0.18190.5357-0.0027-0.0150.65110.08320.3245-13.7301-22.59347.8143
173.0517-0.1170.27931.76290.38363.5864-0.075-0.0599-0.08030.271-0.0307-0.00090.15080.07090.09930.3756-0.0106-0.0470.18980.02170.18052.579-18.091242.058
182.9954-0.2630.4274.58630.14590.3345-0.0264-0.1731-0.38560.40270.0306-0.09380.86290.1586-0.00570.64090.0498-0.03620.25270.01470.27083.7445-30.427439.9301
194.07531.7687-1.16025.11770.88763.67480.05120.2082-0.7118-0.0364-0.041-0.5021.08670.6135-0.27690.95710.2066-0.0560.465-0.19890.446911.1323-35.205325.5198
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 144 through 169 )
2X-RAY DIFFRACTION2chain 'B' and (resid 170 through 187 )
3X-RAY DIFFRACTION3chain 'B' and (resid 188 through 226 )
4X-RAY DIFFRACTION4chain 'B' and (resid 227 through 251 )
5X-RAY DIFFRACTION5chain 'B' and (resid 252 through 299 )
6X-RAY DIFFRACTION6chain 'B' and (resid 300 through 319 )
7X-RAY DIFFRACTION7chain 'A' and (resid 6 through 91 )
8X-RAY DIFFRACTION8chain 'A' and (resid 92 through 106 )
9X-RAY DIFFRACTION9chain 'A' and (resid 107 through 169 )
10X-RAY DIFFRACTION10chain 'A' and (resid 170 through 187 )
11X-RAY DIFFRACTION11chain 'A' and (resid 188 through 209 )
12X-RAY DIFFRACTION12chain 'A' and (resid 210 through 226 )
13X-RAY DIFFRACTION13chain 'A' and (resid 227 through 251 )
14X-RAY DIFFRACTION14chain 'A' and (resid 252 through 284 )
15X-RAY DIFFRACTION15chain 'A' and (resid 285 through 299 )
16X-RAY DIFFRACTION16chain 'A' and (resid 300 through 323 )
17X-RAY DIFFRACTION17chain 'B' and (resid 6 through 91 )
18X-RAY DIFFRACTION18chain 'B' and (resid 92 through 121 )
19X-RAY DIFFRACTION19chain 'B' and (resid 122 through 143 )

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