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- PDB-9ffd: STRUCTURE OF ALDO-KETO REDUCTASE 1C3 (AKR1C3) IN COMPLEX WITH AN ... -

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Basic information

Entry
Database: PDB / ID: 9ffd
TitleSTRUCTURE OF ALDO-KETO REDUCTASE 1C3 (AKR1C3) IN COMPLEX WITH AN INHIBITOR MEDS765
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: 1.75 Å
AuthorsFrydenvang, K. / Hussain, S. / Mirza, O.A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications.
Authors: Pippione, A.C. / Vigato, C. / Tucciarello, C. / Hussain, S. / Salladini, E. / Truong, H.H. / Henriksen, N.M. / Vanzetti, G. / Giordano, G. / Zonari, D. / Mirza, O.A. / Frydenvang, K. / ...Authors: Pippione, A.C. / Vigato, C. / Tucciarello, C. / Hussain, S. / Salladini, E. / Truong, H.H. / Henriksen, N.M. / Vanzetti, G. / Giordano, G. / Zonari, D. / Mirza, O.A. / Frydenvang, K. / Pignochino, Y. / Oliaro-Bosso, S. / Boschi, D. / Lolli, M.L.
History
DepositionMay 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 21, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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)76,80014
Polymers73,7922
Non-polymers3,00712
Water6,287349
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5288
Polymers36,8961
Non-polymers1,6327
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)38,2716
Polymers36,8961
Non-polymers1,3755
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.228, 48.791, 83.314
Angle α, β, γ (deg.)74.12, 85.35, 69.60
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 2 molecules AB

#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: 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 / 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+)

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Non-polymers , 5 types, 361 molecules

#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-A1ICG / ~{N}-(4-bromanyl-2-methyl-phenyl)-2-[methyl-[(8-methyl-7-oxidanyl-2-oxidanylidene-chromen-4-yl)methyl]amino]ethanamide


Mass: 445.306 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21BrN2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 349 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.3 Å3/Da / Density % sol: 46.42 %
Crystal growTemperature: 279 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.1 M MES, 24% PEG3350, PH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 16, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→43.82 Å / Num. obs: 64261 / % possible obs: 97 % / Redundancy: 3.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.043 / Rpim(I) all: 0.027 / Rrim(I) all: 0.051 / Χ2: 1 / Net I/σ(I): 12.4 / Num. measured all: 233261
Reflection shellResolution: 1.75→1.78 Å / % possible obs: 87.8 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.28 / Num. measured all: 10987 / Num. unique obs: 3222 / CC1/2: 0.957 / Rpim(I) all: 0.178 / Rrim(I) all: 0.334 / Χ2: 1.06 / Net I/σ(I) obs: 3.4

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→34.51 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 0.77 / Phase error: 24.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1965 3250 5.07 %
Rwork0.1608 --
obs0.1626 64096 96.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→34.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5061 0 192 349 5602
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055419
X-RAY DIFFRACTIONf_angle_d0.8587352
X-RAY DIFFRACTIONf_dihedral_angle_d16.2372107
X-RAY DIFFRACTIONf_chiral_restr0.05793
X-RAY DIFFRACTIONf_plane_restr0.008931
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.780.29791190.23382355X-RAY DIFFRACTION85
1.78-1.80.26721420.22012615X-RAY DIFFRACTION96
1.8-1.830.24321330.20962571X-RAY DIFFRACTION96
1.83-1.870.23821490.19762660X-RAY DIFFRACTION96
1.87-1.90.26561490.20452579X-RAY DIFFRACTION96
1.9-1.940.23341430.20992656X-RAY DIFFRACTION96
1.94-1.970.23041450.19742571X-RAY DIFFRACTION96
1.98-2.020.24651360.19332699X-RAY DIFFRACTION97
2.02-2.060.22061400.18742615X-RAY DIFFRACTION97
2.06-2.120.18671340.18392671X-RAY DIFFRACTION97
2.12-2.170.20481580.17672641X-RAY DIFFRACTION97
2.17-2.240.22351520.172641X-RAY DIFFRACTION97
2.24-2.310.19491340.16632660X-RAY DIFFRACTION97
2.31-2.390.20781570.16512642X-RAY DIFFRACTION98
2.39-2.490.20211600.16662658X-RAY DIFFRACTION98
2.49-2.60.21991240.16532700X-RAY DIFFRACTION98
2.6-2.740.21951350.16012673X-RAY DIFFRACTION98
2.74-2.910.19151250.162714X-RAY DIFFRACTION98
2.91-3.130.20651640.16292652X-RAY DIFFRACTION99
3.13-3.450.18331590.15752692X-RAY DIFFRACTION99
3.45-3.950.17741420.14372713X-RAY DIFFRACTION99
3.95-4.970.15371360.12212727X-RAY DIFFRACTION99
4.97-34.510.18441140.16082741X-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)
18.30751.301-1.35174.14830.53494.1946-0.14260.68540.2103-0.55680.1746-0.4173-1.36150.5092-0.05710.9687-0.2282-0.07130.47170.06860.3598-16.6121-28.0264-75.651
24.17230.070.65415.08771.27156.5024-0.1237-0.06570.2624-0.12350.0437-0.1215-1.06540.27710.14320.4485-0.04190.0110.20630.03160.2078-21.085-32.1134-63.927
33.8676-0.76030.59196.39132.49385.24210.02880.01090.02170.3060.1479-0.4543-0.10280.1309-0.1850.246-0.0427-0.0270.20160.01230.2014-18.4014-41.3954-61.8658
42.34380.93732.18113.7828-0.21074.77190.56030.3421-0.8950.91560.3042-1.11041.08211.0896-0.17610.99520.2102-0.36730.4174-0.11790.6618-11.4611-60.9064-62.0357
51.0948-0.1674-0.3271.6988-1.2772.45560.2706-0.1439-0.37870.83880.2119-0.40211.5381-0.1352-0.22980.8283-0.0964-0.1760.27810.04970.3522-22.1116-57.8412-61.8192
62.373-0.7163-0.41962.1469-0.58780.40160.10240.04210.08260.5830.8043-0.9063-0.17770.4353-0.71840.6965-0.1019-0.15730.6569-0.17420.6572-6.7706-39.4129-62.9636
71.514-0.08230.44122.8960.42622.7786-0.09450.0977-0.0562-0.2350.03480.17760.1953-0.16740.07210.1903-0.0287-0.01560.18850.01960.1911-33.9168-30.9759-40.2498
84.21774.68143.77986.99663.81396.6968-0.24190.25780.1762-0.39730.2770.2284-0.19740.0324-0.04830.14630.0372-0.00790.17220.03740.2441-31.6972-18.6235-42.8508
98.0077-5.4552-1.63783.79830.48095.8646-0.0288-0.01870.4065-0.1418-0.0795-0.2743-0.06990.66670.22480.2967-0.0713-0.01020.27540.0610.3843-13.9333-12.6001-36.9619
104.17560.13513.96795.8945-1.4328.6156-0.227-0.03930.398-0.1750.01760.3759-0.5678-0.37980.21210.19220.0433-0.00760.1818-0.01840.2791-35.8069-13.1952-35.7956
114.5821-2.7533-0.95455.333-2.75534.9896-0.2978-0.47940.84750.4448-0.05330.0341-1.104-0.39780.36540.39620.0785-0.08610.2682-0.08410.3355-36.8473-9.6953-26.5462
126.1529-4.80212.01417.6068-2.18514.7543-0.2074-0.6950.29950.67830.118-0.0532-0.1564-0.37980.08830.2211-0.05660.00270.2605-0.04280.1944-32.6796-23.924-19.3708
131.94770.24480.40912.80020.23743.58620.0938-0.24-0.24430.2802-0.0864-0.09630.4642-0.06030.01430.2548-0.0452-0.01630.22610.05580.2043-29.7913-38.3576-23.9893
143.11730.6719-0.49723.65010.03569.13390.2709-0.71440.13480.5598-0.31280.02510.03820.03820.02440.4293-0.0517-0.02780.2720.02520.1716-30.188-33.9585-14.5705
154.91853.0586-3.16475.379-2.13872.9601-0.337-1.28860.15830.7922-0.1101-0.5843-0.71750.83670.45630.7306-0.0714-0.32690.75150.09390.6695-20.0891-15.9243-21.9367
162.08350.64591.65572.69142.05413.9599-0.14840.29540.0116-0.31760.218-0.096-0.2428-0.0578-0.08770.377-0.0830.01440.32420.04080.1761-27.1973-46.6863-77.0911
171.1428-0.0302-0.73781.2101-0.99752.0801-0.53330.59610.3629-0.57210.327-0.0512-0.84610.01520.11290.6962-0.1353-0.08590.42290.10110.2796-25.5448-34.1474-78.6168
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'B' and (resid 122 through 157 )
2X-RAY DIFFRACTION2chain 'B' and (resid 158 through 177 )
3X-RAY DIFFRACTION3chain 'B' and (resid 178 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 323 )
7X-RAY DIFFRACTION7chain 'A' and (resid 6 through 91 )
8X-RAY DIFFRACTION8chain 'A' and (resid 92 through 121 )
9X-RAY DIFFRACTION9chain 'A' and (resid 122 through 143 )
10X-RAY DIFFRACTION10chain 'A' and (resid 144 through 169 )
11X-RAY DIFFRACTION11chain 'A' and (resid 170 through 187 )
12X-RAY DIFFRACTION12chain 'A' and (resid 188 through 209 )
13X-RAY DIFFRACTION13chain 'A' and (resid 210 through 285 )
14X-RAY DIFFRACTION14chain 'A' and (resid 286 through 308 )
15X-RAY DIFFRACTION15chain 'A' and (resid 309 through 323 )
16X-RAY DIFFRACTION16chain 'B' and (resid 6 through 91 )
17X-RAY DIFFRACTION17chain 'B' and (resid 92 through 121 )

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