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- PDB-7wqr: Crystal structure of Aldo-keto reductase 1C3 complexed with compo... -

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Basic information

Entry
Database: PDB / ID: 7wqr
TitleCrystal structure of Aldo-keto reductase 1C3 complexed with compound 28
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / aldo-keto reductase / Lipid metabolism / NAD / NADP
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
Chem-4R6 / 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: 2.124 Å
AuthorsJiang, J. / Liu, Y. / He, S. / Chen, Y. / Chu, X. / Liu, Y. / Guo, Q. / Zhao, L. / Feng, F. / Liu, W. ...Jiang, J. / Liu, Y. / He, S. / Chen, Y. / Chu, X. / Liu, Y. / Guo, Q. / Zhao, L. / Feng, F. / Liu, W. / Zhang, X. / Sun, H. / Fang, P.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21977107 China
National Natural Science Foundation of China (NSFC)81973207 China
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer.
Authors: Liu, Y. / Chen, Y. / Jiang, J. / Chu, X. / Guo, Q. / Zhao, L. / Feng, F. / Liu, W. / Zhang, X. / He, S. / Yang, P. / Fang, P. / Sun, H.
History
DepositionJan 25, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 4, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: 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
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)77,6716
Polymers75,4702
Non-polymers2,2004
Water3,675204
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8353
Polymers37,7351
Non-polymers1,1002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-3 kcal/mol
Surface area12950 Å2
MethodPISA
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8353
Polymers37,7351
Non-polymers1,1002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-3 kcal/mol
Surface area13240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.091, 52.741, 77.197
Angle α, β, γ (deg.)77.490, 86.800, 77.850
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: 37735.113 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
#3: Chemical ChemComp-4R6 / ~{N}-(3-chlorophenyl)-2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]benzamide


Mass: 356.803 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H17ClN2O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 204 / 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: 2.06 Å3/Da / Density % sol: 40.41 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: MES pH 6.0, Ammonium chloride, PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL19U1 / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.12→46.67 Å / Num. obs: 29182 / % possible obs: 85.8 % / Redundancy: 1.7 % / Biso Wilson estimate: 31.44 Å2 / CC1/2: 0.828 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.076 / Rrim(I) all: 0.107 / Net I/σ(I): 4.3 / Num. measured all: 49609
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.12-2.241.70.236704441290.8160.2360.3332.383.3
6.72-46.671.90.023190310210.9960.0230.0336.695.2

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Processing

Software
NameVersionClassification
PHENIX1refinement
Aimless0.7.4data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WQM

7wqm


Resolution: 2.124→29.717 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 31.07 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2728 1454 4.99 %
Rwork0.2214 27713 -
obs0.224 29167 85.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 112.06 Å2 / Biso mean: 41.4795 Å2 / Biso min: 16.89 Å2
Refinement stepCycle: final / Resolution: 2.124→29.717 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4935 0 146 204 5285
Biso mean--42.07 42.88 -
Num. residues----629
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.1241-2.20.31531600.2872307895
2.2-2.28810.3229720.3048164251
2.2881-2.39220.36541450.2879310195
2.3922-2.51820.34641650.2861305895
2.5182-2.67590.34351090.2808196493
2.6759-2.88230.30371270.2587241297
2.8823-3.17210.29351670.2497314497
3.1721-3.63040.28061830.2202309496
3.6304-4.57130.24281660.1813309996
4.5713-29.7170.20821600.1717312196
Refinement TLS params.Method: refined / Origin x: -8.0842 Å / Origin y: -9.3237 Å / Origin z: 17.7152 Å
111213212223313233
T0.1728 Å20.0295 Å2-0.0587 Å2-0.2009 Å2-0.0143 Å2--0.226 Å2
L0.463 °20.3046 °2-0.5862 °2-1.0641 °2-0.6585 °2--1.8867 °2
S-0.0513 Å °0.0253 Å °-0.1051 Å °0.1761 Å °-0.0531 Å °-0.0545 Å °-0.364 Å °-0.0756 Å °0.0996 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA6 - 401
2X-RAY DIFFRACTION1allA501
3X-RAY DIFFRACTION1allB6 - 401
4X-RAY DIFFRACTION1allB501
5X-RAY DIFFRACTION1allC1 - 218

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