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

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Basic information

Entry
Database: PDB / ID: 7wqs
TitleCrystal structure of Aldo-keto reductase 1C3 complexed with compound 25
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 / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / negative regulation of retinoic acid biosynthetic process ...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 / 15-hydroxyprostaglandin-D dehydrogenase (NADP+) activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / negative regulation of retinoic acid biosynthetic process / 3alpha(17beta)-hydroxysteroid dehydrogenase (NAD+) / 5alpha-androstane-3beta,17beta-diol dehydrogenase activity / delta4-3-oxosteroid 5beta-reductase activity / farnesol catabolic process / geranylgeranyl reductase activity / 3alpha-hydroxysteroid 3-dehydrogenase / phenanthrene 9,10-monooxygenase activity / macromolecule metabolic process / regulation of testosterone biosynthetic process / cellular response to jasmonic acid stimulus / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase activity / dihydrotestosterone 17-beta-dehydrogenase activity / androsterone dehydrogenase activity / testosterone dehydrogenase (NAD+) activity / testosterone biosynthetic process / RA biosynthesis pathway / regulation of retinoic acid receptor signaling pathway / cellular response to prostaglandin D stimulus / ketosteroid monooxygenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / retinal metabolic process / testosterone 17-beta-dehydrogenase (NADP+) activity / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / estradiol 17-beta-dehydrogenase [NAD(P)] activity / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / aldo-keto reductase (NADPH) activity / cyclooxygenase pathway / all-trans-retinol dehydrogenase (NAD+) activity / prostaglandin H2 endoperoxidase reductase activity / positive regulation of endothelial cell apoptotic process / 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 / Retinoid metabolism and transport / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / keratinocyte differentiation / cellular response to calcium ion / cellular response to starvation / 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-4ZI / 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: 2.07 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 26, 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)77,6626
Polymers75,4702
Non-polymers2,1924
Water10,485582
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8313
Polymers37,7351
Non-polymers1,0962
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-3 kcal/mol
Surface area13150 Å2
MethodPISA
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8313
Polymers37,7351
Non-polymers1,0962
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-3 kcal/mol
Surface area13140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.949, 49.428, 83.269
Angle α, β, γ (deg.)74.660, 74.350, 61.690
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 / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-4ZI / 2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]-~{N}-(3-methoxyphenyl)benzamide


Mass: 352.384 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N2O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 582 / 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: 2.23 Å3/Da / Density % sol: 44.93 %
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: SSRF / Beamline: BL02U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.07→19.93 Å / Num. obs: 36183 / % possible obs: 90.9 % / Redundancy: 2.1 % / Biso Wilson estimate: 16.42 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.017 / Rpim(I) all: 0.015 / Rrim(I) all: 0.023 / Net I/σ(I): 18.4 / Num. measured all: 75927 / Scaling rejects: 1
Reflection shell

Diffraction-ID: 1 / Redundancy: 2.1 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.07-2.130.031589028440.9970.0280.0421391.7
9.02-19.930.0168704060.9990.0150.0222582.7

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Processing

Software
NameVersionClassification
PHENIX1refinement
Aimless0.7.7data scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7WQM

7wqm


Resolution: 2.07→19.929 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 2 / Phase error: 19.39 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1999 1861 5.14 %
Rwork0.168 34320 -
obs0.1697 36181 91.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 76.15 Å2 / Biso mean: 20.7705 Å2 / Biso min: 7.17 Å2
Refinement stepCycle: final / Resolution: 2.07→19.929 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4958 0 148 582 5688
Biso mean--21.13 32.43 -
Num. residues----628
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.07-2.12590.2211410.1807267192
2.1259-2.18840.25531570.1851269894
2.1884-2.2590.21951640.1801264092
2.259-2.33960.22481080.1832270291
2.3396-2.43310.23231320.1851258089
2.4331-2.54360.22291330.1868252787
2.5436-2.67740.23411380.1804272494
2.6774-2.84470.23141530.1796266792
2.8447-3.06370.20091310.1712265691
3.0637-3.37060.18371210.1682254087
3.3706-3.85530.18541350.1495273594
3.8553-4.84570.16311560.1393253388
4.8457-19.9290.17251920.1667264793
Refinement TLS params.Method: refined / Origin x: -5.4862 Å / Origin y: -11.0069 Å / Origin z: -19.2453 Å
111213212223313233
T0.0781 Å20.0034 Å20.0147 Å2-0.0717 Å20.0275 Å2--0.1064 Å2
L0.2765 °20.1544 °20.3401 °2-0.3421 °20.4892 °2--1.2603 °2
S-0.0024 Å °0.0137 Å °-0.0218 Å °0.0004 Å °0.0211 Å °-0.0089 Å °-0.0118 Å °0.0877 Å °-0.0136 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA6 - 601
2X-RAY DIFFRACTION1allB6 - 501
3X-RAY DIFFRACTION1allC1 - 696

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