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

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Basic information

Entry
Database: PDB / ID: 7wqm
TitleCrystal structure of Aldo-keto reductase 1C3 complexed with compound 24
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 / 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 / testosterone dehydrogenase (NADP+) activity / androsterone dehydrogenase [NAD(P)+] activity / ketosteroid monooxygenase activity / regulation of testosterone biosynthetic process / RA biosynthesis pathway / testosterone biosynthetic process / : / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / testosterone dehydrogenase (NAD+) activity / regulation of retinoic acid receptor signaling pathway / cellular response to prostaglandin D stimulus / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / retinal metabolic process / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / estradiol 17-beta-dehydrogenase [NAD(P)+] activity / all-trans-retinol dehydrogenase (NAD+) 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 / bile acid binding / daunorubicin metabolic process / doxorubicin metabolic process / retinal dehydrogenase (NAD+) activity / aldose reductase (NADPH) activity / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / 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
Chem-4IV / 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: 2.13 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)77,6626
Polymers75,4702
Non-polymers2,1924
Water7,062392
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 area1220 Å2
ΔGint-3 kcal/mol
Surface area13070 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 area1210 Å2
ΔGint-3 kcal/mol
Surface area13310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.827, 49.692, 83.075
Angle α, β, γ (deg.)74.690, 74.580, 61.320
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-4IV / 2-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]-~{N}-(2-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


Mass: 18.015 Da / Num. of mol.: 392 / 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: 44.82 %
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: BL19U1 / Wavelength: 0.9791 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 8, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.13→79.04 Å / Num. obs: 34379 / % possible obs: 93.6 % / Redundancy: 1.6 % / Biso Wilson estimate: 17.89 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.067 / Rrim(I) all: 0.094 / Net I/σ(I): 3.2 / Num. measured all: 55827
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
2.13-2.241.60.2825250990.8550.20.2832.694.7
6.72-79.041.80.034194610530.9930.0340.049489.8

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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: 4DBU

4dbu


Resolution: 2.13→31.768 Å / SU ML: 0.18 / Cross valid method: THROUGHOUT / σ(F): 1.98 / Phase error: 19.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2067 1671 4.86 %
Rwork0.1719 32691 -
obs0.1735 34362 93.58 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 75.11 Å2 / Biso mean: 22.5212 Å2 / Biso min: 8.13 Å2
Refinement stepCycle: final / Resolution: 2.13→31.768 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4983 0 148 392 5523
Biso mean--24.07 32.31 -
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 (%)
2.13-2.18760.24281380.1943278595
2.1876-2.25820.25071120.1989276394
2.2582-2.33890.25511730.1983270994
2.3389-2.43250.21881580.19268593
2.4325-2.54320.21831540.1817270393
2.5432-2.67720.20551390.1841274394
2.6772-2.84480.22771330.1848274594
2.8448-3.06430.18831670.1766275395
3.0643-3.37240.19831580.1673273895
3.3724-3.85960.17721170.149272993
3.8596-4.85990.1716730.1449272192
4.8599-31.760.20081490.1727261791
Refinement TLS params.Method: refined / Origin x: 3.9765 Å / Origin y: 10.6164 Å / Origin z: 19.4028 Å
111213212223313233
T0.0746 Å20.0094 Å20.008 Å2-0.1135 Å20.026 Å2--0.1042 Å2
L0.2194 °20.155 °20.2826 °2-0.3822 °20.4699 °2--1.0341 °2
S-0.0003 Å °0.0009 Å °-0.0161 Å °0.0045 Å °0.0045 Å °0.0092 Å °0.0043 Å °0.0594 Å °-0.004 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA6 - 319
2X-RAY DIFFRACTION1allA401 - 501
3X-RAY DIFFRACTION1allB6 - 319
4X-RAY DIFFRACTION1allB401 - 501
5X-RAY DIFFRACTION1allC1 - 440

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