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- PDB-8bbs: Structure of AKR1C3 in complex with a bile acid fused tetrazole i... -

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Entry
Database: PDB / ID: 8bbs
TitleStructure of AKR1C3 in complex with a bile acid fused tetrazole inhibitor
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / AKR1C3 / aldo-keto reductase / steroid metabolism / bile acid / tetrazole / cancer
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. / 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 / Chem-QBO / Aldo-keto reductase family 1 member C3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.4 Å
AuthorsPetri, E.T. / Skerlova, J. / Marinovic, M. / Brynda, J. / Kugler, M. / Skoric, D. / Bekic, S. / Celic, A.S. / Rezacova, P.
Funding support Serbia, European Union, 3items
OrganizationGrant numberCountry
Other government451-03-9/2021-14/ 200125 Serbia
Other government142-451-3177/2020-03 Serbia
Other governmentLX22NPO5102European Union
CitationJournal: Rsc Med Chem / Year: 2023
Title: X-ray structure of human aldo-keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis.
Authors: Marinovic, M.A. / Bekic, S.S. / Kugler, M. / Brynda, J. / Skerlova, J. / Skoric, D.D. / Rezacova, P. / Petri, E.T. / Celic, A.S.
History
DepositionOct 14, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 2.0May 24, 2023Group: Non-polymer description / Category: chem_comp / Item: _chem_comp.formula
Revision 2.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Aldo-keto reductase family 1 member C3
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)76,93215
Polymers74,3772
Non-polymers2,55513
Water13,097727
1
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4547
Polymers37,1891
Non-polymers1,2666
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,4778
Polymers37,1891
Non-polymers1,2897
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.462, 51.413, 77.879
Angle α, β, γ (deg.)77.260, 86.740, 77.630
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 / DD-3 / DD3 / Dihydrodiol dehydrogenase type I / HA1753 / Prostaglandin F synthase / PGFS / Testosterone 17-beta-dehydrogenase 5


Mass: 37188.508 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: The N-terminal sequence GSH is a cloning artefact / Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS / Plasmid: pET28b(+) / Production host: Escherichia coli BL21(DE3) (bacteria)
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-QBO / (4~{R})-4-[(1~{R},2~{S},5~{R},6~{R},13~{S},14~{S},17~{R},19~{R})-6,14-dimethyl-17-oxidanyl-7,8,9,10-tetrazapentacyclo[11.8.0.0^{2,6}.0^{7,11}.0^{14,19}]henicosa-8,10-dien-5-yl]pentanoic acid


Mass: 430.584 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H38N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 727 / 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: 2.02 Å3/Da / Density % sol: 39.23 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 12.5% w/v PEG 1000, 12.5% w/v PEG 3350, 12.5% v/v MPD and 0.02 M each of DL-glutamic acid monohydrate, DL-alanine, glycine, DL-lysine monohydrochloride, and DL-serine; in 0.1 M bicine/Trizma base, pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 26, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.4→45.93 Å / Num. obs: 107028 / % possible obs: 93.1 % / Redundancy: 3.582 % / Biso Wilson estimate: 21.72 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.058 / Rrim(I) all: 0.068 / Χ2: 0.806 / Net I/σ(I): 12.49 / Num. measured all: 383345
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.4-1.483.6380.5822.136276618613172520.8280.67992.7
1.48-1.593.5680.363.335664317444158770.9460.42191
1.59-1.713.6630.2365.25622316320153470.9660.27594
1.71-1.883.5540.1427.924871014932137040.9970.16691.8
1.88-2.13.6230.08714.174665513512128760.9920.10295.3
2.1-2.423.4510.0619.963776411931109420.9950.0791.7
2.42-2.973.6220.04426.64351491009197040.9970.05296.2
2.97-4.183.4450.03333.9125067779472760.9980.03993.4
4.18-45.933.5480.02937.6514368431440500.9980.03493.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMAC5.8.0232refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ZQ5

1zq5


Resolution: 1.4→45.93 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.971 / SU R Cruickshank DPI: 0.062 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.062 / ESU R Free: 0.062 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1775 1533 1.4 %RANDOM
Rwork0.1546 ---
obs0.155 105499 93.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 72.96 Å2 / Biso mean: 17.31 Å2 / Biso min: 8.77 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0.02 Å20.01 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 1.4→45.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5072 0 167 728 5967
Biso mean--17.89 30.4 -
Num. residues----632
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0135667
X-RAY DIFFRACTIONr_bond_other_d0.0340.0175258
X-RAY DIFFRACTIONr_angle_refined_deg1.7431.697740
X-RAY DIFFRACTIONr_angle_other_deg2.2521.61912278
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0035692
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.74622.072304
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.705151001
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2721541
X-RAY DIFFRACTIONr_chiral_restr0.0920.2718
X-RAY DIFFRACTIONr_gen_planes_refined0.010.026332
X-RAY DIFFRACTIONr_gen_planes_other0.0150.021195
LS refinement shellResolution: 1.4→1.436 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.258 113 -
Rwork0.267 7795 -
all-7908 -
obs--93.06 %

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