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- PDB-7x3m: Crystal structure of Aldo-keto reductase 1C3 complexed with compo... -

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Basic information

Entry
Database: PDB / ID: 7x3m
TitleCrystal structure of Aldo-keto reductase 1C3 complexed with compound S07045
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / 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-8IH / 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: 2.694 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. / Fang, P. / Sun, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21977107 China
CitationJournal: J.Med.Chem. / Year: 2023
Title: Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment.
Authors: He, S. / Chu, X. / Wu, Y. / Jiang, J. / Fang, P. / Chen, Y. / Liu, Y. / Qiu, Z. / Xiao, Y. / Li, Z. / Pan, D. / Zhang, Q. / Xie, H. / Xing, S. / Feng, F. / Liu, W. / Guo, Q. / Zhao, L. / Yang, P. / Sun, H.
History
DepositionMar 1, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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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)77,7116
Polymers75,4702
Non-polymers2,2414
Water2,540141
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8563
Polymers37,7351
Non-polymers1,1212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-4 kcal/mol
Surface area13390 Å2
MethodPISA
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,8563
Polymers37,7351
Non-polymers1,1212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-4 kcal/mol
Surface area13380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.066, 105.335, 75.436
Angle α, β, γ (deg.)90.000, 102.360, 90.000
Int Tables number4
Space group name H-MP1211

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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-8IH / (2~{R})-2-[4-[3,5-bis(chloranyl)phenyl]-3-(trifluoromethyl)phenyl]butanoic acid


Mass: 377.185 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H13Cl2F3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 141 / 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: 2.52 Å3/Da / Density % sol: 51.25 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6 / 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: BL17U1 / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER2 S 9M / 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: 2.69→60.38 Å / Num. obs: 17327 / % possible obs: 84 % / Redundancy: 2 % / Biso Wilson estimate: 25.47 Å2 / CC1/2: 0.879 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.092 / Rrim(I) all: 0.141 / Net I/σ(I): 6.1 / Num. measured all: 35235
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
2.69-2.841.80.17315217660.9680.1320.2164.359.3
8.52-60.382.30.05213836120.990.040.0669.193.2

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Processing

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

7wqm


Resolution: 2.694→31.697 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 23.61 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2297 831 4.82 %
Rwork0.1897 16408 -
obs0.1917 17239 82.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.19 Å2 / Biso mean: 31.9353 Å2 / Biso min: 13.18 Å2
Refinement stepCycle: final / Resolution: 2.694→31.697 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4974 0 144 141 5259
Biso mean--39.75 27.02 -
Num. residues----630
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.694-2.86220.3072960.2192190558
2.8622-3.0830.25641170.2158207964
3.083-3.39290.27461500.2276314796
3.3929-3.88320.24831720.2016305593
3.8832-4.88950.2091560.1638310094
4.8895-31.6970.16751400.1629312293
Refinement TLS params.Method: refined / Origin x: 17.5396 Å / Origin y: -10.5133 Å / Origin z: 21.2571 Å
111213212223313233
T0.133 Å20.003 Å2-0.0036 Å2-0.1378 Å2-0.0208 Å2--0.2286 Å2
L0.1271 °20.0531 °2-0.0305 °2-0.1528 °2-0.229 °2--0.5025 °2
S0.0018 Å °0.0041 Å °-0.0023 Å °-0.0313 Å °-0.0211 Å °0.0108 Å °0.0731 Å °0.0344 Å °0.0194 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA6 - 320
2X-RAY DIFFRACTION1allA401 - 501
3X-RAY DIFFRACTION1allB6 - 320
4X-RAY DIFFRACTION1allB401 - 501
5X-RAY DIFFRACTION1allC2 - 386

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