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- PDB-7c7h: Crystal structures of AKR1C3 ternary complex with NADP+ and the c... -

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Basic information

Entry
Database: PDB / ID: 7c7h
TitleCrystal structures of AKR1C3 ternary complex with NADP+ and the chromene derivative 2l
ComponentsAldo-keto reductase family 1 member C3
KeywordsOXIDOREDUCTASE / 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 / 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+) / androsterone dehydrogenase [NAD(P)+] activity / regulation of testosterone biosynthetic process / ketosteroid monooxygenase activity / RA biosynthesis pathway / cellular response to prostaglandin D stimulus / testosterone biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / 3alpha(or 20beta)-hydroxysteroid dehydrogenase / androstan-3-alpha,17-beta-diol dehydrogenase (NAD+) activity / testosterone dehydrogenase (NAD+) activity / regulation of retinoic acid receptor signaling pathway / testosterone dehydrogenase [NAD(P)+] activity / retinal metabolic process / testosterone 17-beta-dehydrogenase (NADP+) activity / progesterone metabolic process / 17beta-estradiol 17-dehydrogenase / Synthesis of Prostaglandins (PG) and Thromboxanes (TX) / cyclooxygenase pathway / all-trans-retinol dehydrogenase (NAD+) activity / estradiol 17-beta-dehydrogenase [NAD(P)+] 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 / daunorubicin metabolic process / doxorubicin metabolic process / retinal dehydrogenase activity / bile acid binding / oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor / aldose reductase (NADPH) activity / retinoid metabolic process / 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 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-FJU / 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: 1.86 Å
AuthorsIrie, K. / Toyooka, N. / Endo, S.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)17K11151 Japan
Japan Society for the Promotion of Science (JSPS)JP26460149 Japan
Japan Agency for Medical Research and Development (AMED)JP17lm0203002 Japan
CitationJournal: J.Med.Chem. / Year: 2020
Title: Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer.
Authors: Endo, S. / Oguri, H. / Segawa, J. / Kawai, M. / Hu, D. / Xia, S. / Okada, T. / Irie, K. / Fujii, S. / Gouda, H. / Iguchi, K. / Matsukawa, T. / Fujimoto, N. / Nakayama, T. / Toyooka, N. / ...Authors: Endo, S. / Oguri, H. / Segawa, J. / Kawai, M. / Hu, D. / Xia, S. / Okada, T. / Irie, K. / Fujii, S. / Gouda, H. / Iguchi, K. / Matsukawa, T. / Fujimoto, N. / Nakayama, T. / Toyooka, N. / Matsunaga, T. / Ikari, A.
History
DepositionMay 25, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 7, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)76,2046
Polymers74,1012
Non-polymers2,1034
Water5,729318
1
A: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1023
Polymers37,0501
Non-polymers1,0522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-5 kcal/mol
Surface area13860 Å2
MethodPISA
2
B: Aldo-keto reductase family 1 member C3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1023
Polymers37,0501
Non-polymers1,0522
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-4 kcal/mol
Surface area13990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.121, 52.314, 76.683
Angle α, β, γ (deg.)77.254, 86.161, 77.639
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z

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Components

#1: Protein Aldo-keto reductase family 1 member C3 / Trans-1 / 2-dihydrobenzene-1 / 2-diol dehydrogenase


Mass: 37050.359 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, trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
#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-FJU / 2-azanylidene-N-(3-ethylphenyl)-8-oxidanyl-chromene-3-carboxamide / N-(3-ethylphenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide


Mass: 308.331 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H16N2O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 318 / 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: 2.07 Å3/Da / Density % sol: 40.55 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 25-30% (w/v) polyethylene glycol 3350 (PEG3350), 200 mM sodium acetate and 100 mM cacodylate, pH 6.6

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.86→46.3 Å / Num. obs: 47872 / % possible obs: 96.69 % / Redundancy: 3.4 % / Biso Wilson estimate: 34 Å2 / CC1/2: 0.973 / Rmerge(I) obs: 0.1077 / Rrim(I) all: 0.1294 / Net I/σ(I): 8.98
Reflection shellResolution: 1.86→1.92 Å / Rmerge(I) obs: 0.8658 / Num. unique obs: 4670 / CC1/2: 0.863 / Rrim(I) all: 1.029

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
REFMAC5refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2c7g

2c7g


Resolution: 1.86→46.3 Å / SU ML: 0.3561 / Cross valid method: FREE R-VALUE / σ(F): 1.97 / Phase error: 34.8116 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.2642 2322 4.83 %
Rwork0.2173 45742 -
obs0.2196 47872 96.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 42.62 Å2
Refinement stepCycle: LAST / Resolution: 1.86→46.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5159 0 71 318 5548
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00985360
X-RAY DIFFRACTIONf_angle_d1.29117276
X-RAY DIFFRACTIONf_chiral_restr0.082784
X-RAY DIFFRACTIONf_plane_restr0.007927
X-RAY DIFFRACTIONf_dihedral_angle_d23.50472027
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.86-1.90.3861210.37762578X-RAY DIFFRACTION92.12
1.9-1.940.40171250.36142680X-RAY DIFFRACTION95.96
1.94-1.990.38971280.31822686X-RAY DIFFRACTION96.57
1.99-2.040.36951290.32272693X-RAY DIFFRACTION96.64
2.04-2.090.34151480.31632699X-RAY DIFFRACTION96.51
2.09-2.150.33261390.30062664X-RAY DIFFRACTION96.82
2.15-2.220.40471400.30532714X-RAY DIFFRACTION96.78
2.22-2.30.37681280.30052671X-RAY DIFFRACTION96.75
2.3-2.390.30311450.27742719X-RAY DIFFRACTION97.18
2.39-2.50.37111460.28142720X-RAY DIFFRACTION97.19
2.5-2.640.32951250.26622675X-RAY DIFFRACTION97.36
2.64-2.80.27571350.25232713X-RAY DIFFRACTION97
2.8-3.020.32141390.22172700X-RAY DIFFRACTION97.69
3.02-3.320.23031430.2152737X-RAY DIFFRACTION97.36
3.32-3.80.24881340.18162681X-RAY DIFFRACTION96.9
3.8-4.790.1941400.1532706X-RAY DIFFRACTION97.17
4.79-46.30.19211570.1522706X-RAY DIFFRACTION97.98

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