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- PDB-6a7a: AKR1C1 complexed with new inhibitor with novel scaffold -

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Basic information

Entry
Database: PDB / ID: 6a7a
TitleAKR1C1 complexed with new inhibitor with novel scaffold
ComponentsAldo-keto reductase family 1 member C1
KeywordsOXIDOREDUCTASE / Aldo-keto reductase family 1 member C1 / 20-alpha-hydroxysteroid Dehydrogenase / alpha-HSD
Function / homology
Function and homology information


3beta-hydroxy-5beta-steroid dehydrogenase activity / 20alpha-hydroxysteroid dehydrogenase / 17-alpha,20-alpha-dihydroxypregn-4-en-3-one dehydrogenase activity / steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor / androsterone dehydrogenase (B-specific) activity / indanol dehydrogenase / trans-1,2-dihydrobenzene-1,2-diol dehydrogenase / 3(or 17)alpha-hydroxysteroid dehydrogenase / trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity / 3(or 17)beta-hydroxysteroid dehydrogenase ...3beta-hydroxy-5beta-steroid dehydrogenase activity / 20alpha-hydroxysteroid dehydrogenase / 17-alpha,20-alpha-dihydroxypregn-4-en-3-one dehydrogenase activity / steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor / androsterone dehydrogenase (B-specific) activity / indanol dehydrogenase / trans-1,2-dihydrobenzene-1,2-diol dehydrogenase / 3(or 17)alpha-hydroxysteroid dehydrogenase / trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity / 3(or 17)beta-hydroxysteroid dehydrogenase / indanol dehydrogenase activity / testosterone dehydrogenase [NAD(P)] activity / 3beta(or 20alpha)-hydroxysteroid dehydrogenase / 5alpha-androstane-3beta,17beta-diol dehydrogenase activity / 3alpha-hydroxysteroid 3-dehydrogenase / response to organophosphorus / phenanthrene 9,10-monooxygenase activity / 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 / intestinal cholesterol absorption / 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 / carboxylic acid binding / estradiol 17-beta-dehydrogenase [NAD(P)] activity / aldo-keto reductase (NADPH) activity / bile acid metabolic process / bile acid and bile salt transport / 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 / bile acid binding / aldose reductase (NADPH) activity / Prednisone ADME / retinoid metabolic process / prostaglandin 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 / digestion / epithelial cell differentiation / xenobiotic metabolic process / cholesterol homeostasis / positive regulation of reactive oxygen species metabolic process / extracellular exosome / cytosol
Similarity search - Function
Aldo-keto reductase family 1 member C / Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / NADP-dependent oxidoreductase domain / 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 ...Aldo-keto reductase family 1 member C / Aldo/keto reductase family putative active site signature. / Aldo/keto reductase family signature 1. / NADP-dependent oxidoreductase domain / 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 / TIM Barrel / Alpha-Beta Barrel / Alpha Beta
Similarity search - Domain/homology
Chem-9S0 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member C1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsZheng, X. / Zhao, Y. / Zhang, H. / Chen, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China81602968 China
CitationJournal: Bioorg.Med.Chem. / Year: 2018
Title: Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors.
Authors: Zheng, X. / Jiang, Z. / Li, X. / Zhang, C. / Li, Z. / Wu, Y. / Wang, X. / Zhang, C. / Luo, H.B. / Xu, J. / Wu, D.
History
DepositionJul 2, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 3, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2020Group: Database references / Category: 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 22, 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 C1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8713
Polymers38,7561
Non-polymers1,1152
Water2,900161
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-5 kcal/mol
Surface area13690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.124, 83.517, 48.938
Angle α, β, γ (deg.)90.00, 90.32, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Aldo-keto reductase family 1 member C1 / 20-alpha-hydroxysteroid dehydrogenase / 20-alpha-HSD / Chlordecone reductase homolog HAKRC / ...20-alpha-hydroxysteroid dehydrogenase / 20-alpha-HSD / Chlordecone reductase homolog HAKRC / Dihydrodiol dehydrogenase 1/2 / DD1/DD2 / High-affinity hepatic bile acid-binding protein / HBAB / Indanol dehydrogenase / Trans-1 / 2-dihydrobenzene-1 / 2-diol dehydrogenase


Mass: 38756.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1C1, DDH, DDH1 / Production host: Escherichia coli (E. coli)
References: UniProt: Q04828, Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor, 20alpha-hydroxysteroid dehydrogenase, indanol dehydrogenase, trans-1,2- ...References: UniProt: Q04828, Oxidoreductases; Acting on the CH-OH group of donors; With NAD+ or NADP+ as acceptor, 20alpha-hydroxysteroid dehydrogenase, indanol dehydrogenase, trans-1,2-dihydrobenzene-1,2-diol dehydrogenase
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-9S0 / (4R)-6-amino-4-(4-hydroxy-3-methoxy-5-nitrophenyl)-3-propyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile


Mass: 371.347 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N5O5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 161 / Source method: isolated from a natural source / Formula: H2O

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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: 2.21 Å3/Da / Density % sol: 44.29 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop
Details: 23-27% (w/v) PEG 4000, 100 mM Hepes, 10mM CaCl2, 0.4M NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION NOVA / Wavelength: 1.5418 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Aug 29, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.37→24.704 Å / Num. obs: 12817 / % possible obs: 99.7 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.19 / Net I/σ(I): 9.9
Reflection shellResolution: 2.37→2.53 Å / Redundancy: 7.9 % / Rmerge(I) obs: 0.26 / Mean I/σ(I) obs: 6.1 / Num. unique obs: 2026

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
CrysalisProdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NTY

3nty


Resolution: 2.37→24.704 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 22.14
RfactorNum. reflection% reflection
Rfree0.2233 1277 9.96 %
Rwork0.1552 --
obs0.162 12815 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.37→24.704 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2546 0 75 161 2782
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072685
X-RAY DIFFRACTIONf_angle_d1.013650
X-RAY DIFFRACTIONf_dihedral_angle_d12.6481050
X-RAY DIFFRACTIONf_chiral_restr0.037397
X-RAY DIFFRACTIONf_plane_restr0.005508
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.37-2.46490.26221430.16281286X-RAY DIFFRACTION100
2.4649-2.57690.24261370.17451284X-RAY DIFFRACTION100
2.5769-2.71260.26581430.17371275X-RAY DIFFRACTION100
2.7126-2.88230.24941410.17191280X-RAY DIFFRACTION100
2.8823-3.10450.26771420.17351270X-RAY DIFFRACTION100
3.1045-3.41620.22021400.15841277X-RAY DIFFRACTION100
3.4162-3.90880.21411510.15241300X-RAY DIFFRACTION100
3.9088-4.91830.1831410.13041282X-RAY DIFFRACTION100
4.9183-24.70560.18511390.13971284X-RAY DIFFRACTION98

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