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- PDB-3g1r: Crystal structure of human liver 5beta-reductase (AKR1D1) in comp... -

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Basic information

Entry
Database: PDB / ID: 3g1r
TitleCrystal structure of human liver 5beta-reductase (AKR1D1) in complex with NADP and Finasteride. Resolution 1.70 A
Components3-oxo-5-beta-steroid 4-dehydrogenase
KeywordsOXIDOREDUCTASE / FINASTERIDE complex / Bile acid catabolism / Cytoplasm / Disease mutation / Intrahepatic cholestasis / Lipid metabolism / NADP / Steroid metabolism
Function / homology
Function and homology information


Delta4-3-oxosteroid 5beta-reductase / C21-steroid hormone metabolic process / bile acid catabolic process / steroid dehydrogenase activity / Delta4-3-oxosteroid 5beta-reductase activity / ketosteroid monooxygenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / aldo-keto reductase (NADPH) activity / bile acid biosynthetic process / aldose reductase (NADPH) activity ...Delta4-3-oxosteroid 5beta-reductase / C21-steroid hormone metabolic process / bile acid catabolic process / steroid dehydrogenase activity / Delta4-3-oxosteroid 5beta-reductase activity / ketosteroid monooxygenase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / aldo-keto reductase (NADPH) activity / bile acid biosynthetic process / aldose reductase (NADPH) activity / androgen metabolic process / Synthesis of bile acids and bile salts via 27-hydroxycholesterol / cholesterol catabolic process / Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol / digestion / steroid binding / cytosol
Similarity search - Function
Aldo-keto reductase family 1 member D1 / 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 D1 / 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-FIT / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Aldo-keto reductase family 1 member D1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.701 Å
AuthorsDi Costanzo, L. / Drury, J.E. / Penning, T.M. / Christianson, D.W.
CitationJournal: J.Biol.Chem. / Year: 2009
Title: Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex.
Authors: Drury, J.E. / Di Costanzo, L. / Penning, T.M. / Christianson, D.W.
History
DepositionJan 30, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 9, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 24, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3-oxo-5-beta-steroid 4-dehydrogenase
B: 3-oxo-5-beta-steroid 4-dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,0585
Polymers79,1992
Non-polymers1,8593
Water13,583754
1
A: 3-oxo-5-beta-steroid 4-dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3432
Polymers39,5991
Non-polymers7431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: 3-oxo-5-beta-steroid 4-dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,7153
Polymers39,5991
Non-polymers1,1162
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.892, 109.877, 128.961
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein 3-oxo-5-beta-steroid 4-dehydrogenase / Delta(4)-3-ketosteroid 5-beta-reductase / Delta(4)-3-oxosteroid 5-beta-reductase / Aldo-keto ...Delta(4)-3-ketosteroid 5-beta-reductase / Delta(4)-3-oxosteroid 5-beta-reductase / Aldo-keto reductase family 1 member D1


Mass: 39599.258 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AKR1D1, SRD5B1 / Plasmid: PET15B / Production host: Escherichia coli (E. coli)
References: UniProt: P51857, Delta4-3-oxosteroid 5beta-reductase
#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-FIT / (4aR,4bS,6aS,7S,9aS,9bS,11aR)-N-tert-butyl-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxamide / FINASTERIDE


Mass: 372.544 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H36N2O2 / Comment: medication*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 754 / 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: 2.23 Å3/Da / Density % sol: 44.88 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.4
Details: The ternary complexes of AKR1D1-NADP+-finasteride was crystallized by the hanging drop vapor diffusion method at 4 C. Drops containing 3.0 L of enzyme solution [5.0 mg/mL AKR1D1, 2.0 mM ...Details: The ternary complexes of AKR1D1-NADP+-finasteride was crystallized by the hanging drop vapor diffusion method at 4 C. Drops containing 3.0 L of enzyme solution [5.0 mg/mL AKR1D1, 2.0 mM NADP+, 0.5 mM finasteride, 10.0 mM Tris (pH 7.4)] and 4.0 L of precipitant buffer [0.1 M TRIS-HCl (pH 7.0), 10-20% (wt/vol) PEG 4000, 10% iso-propanol] were equilibrated against a 1 mL reservoir of precipitant buffer. Crystals of the AKR1D1-NADP+-finasteride, complex were soaked for 24 hours in the same mother liquor solution augmented with 2.0 mm NADP+, 2.0 mM finasteride and 30% iso-propanol, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jun 23, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→30 Å / Num. all: 76941 / Num. obs: 76941 / % possible obs: 97.8 % / Redundancy: 5 % / Biso Wilson estimate: 14.49 Å2 / Rmerge(I) obs: 0.049 / Rsym value: 0.049 / Net I/σ(I): 25.3
Reflection shellResolution: 1.7→1.76 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 3.5 / Rsym value: 0.35 / % possible all: 92.9

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine)refinement
CNSrefinement
ADSCQuantumdata collection
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3CMF

3cmf


Resolution: 1.701→24.337 Å / Occupancy max: 1 / Occupancy min: 0.39 / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 0.1 / Phase error: 19.22 / Stereochemistry target values: ML
Details: The binding steroid pocket of monomer A showed a discontinuous peak that was not possible to fit with finasteride molecule or a different ligand.
RfactorNum. reflection% reflectionSelection details
Rfree0.205 3717 5.05 %RANDOM
Rwork0.175 69843 --
obs0.177 73560 93.51 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 31.45 Å2 / ksol: 0.327 e/Å3
Displacement parametersBiso max: 92.59 Å2 / Biso mean: 18.375 Å2 / Biso min: 5.08 Å2
Baniso -1Baniso -2Baniso -3
1-0.777 Å2-0 Å2-0 Å2
2---0.493 Å2-0 Å2
3----0.285 Å2
Refinement stepCycle: LAST / Resolution: 1.701→24.337 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5263 0 123 754 6140
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0065527
X-RAY DIFFRACTIONf_angle_d0.9927524
X-RAY DIFFRACTIONf_chiral_restr0.067796
X-RAY DIFFRACTIONf_plane_restr0.006955
X-RAY DIFFRACTIONf_dihedral_angle_d16.952212
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 27

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.701-1.7230.231100.192173228378
1.723-1.7450.2421020.1942251235383
1.745-1.7690.2251250.192312243784
1.769-1.7940.2211160.1872273238984
1.794-1.8210.2341290.1882362249186
1.821-1.850.2441150.1932370248586
1.85-1.880.2261220.1922363248587
1.88-1.9120.2431420.1832468261090
1.912-1.9470.1911170.1792518263591
1.947-1.9850.2151420.1812527266993
1.985-2.0250.1991390.1812567270694
2.025-2.0690.221280.1832670279896
2.069-2.1170.2351320.1762646277896
2.117-2.170.2291600.1752657281796
2.17-2.2290.1971370.1722649278697
2.229-2.2940.2391530.1812652280596
2.294-2.3680.2021350.182684281997
2.368-2.4530.2031460.1712670281697
2.453-2.5510.2331500.1762702285298
2.551-2.6670.2251630.182687285098
2.667-2.8070.1961350.1842748288398
2.807-2.9830.2011790.182685286498
2.983-3.2130.2071490.1792761291099
3.213-3.5350.1881400.17528262966100
3.535-4.0450.1651500.15327992949100
4.045-5.0880.1421450.13828442989100
5.088-24.340.1811560.152979313599

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