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- PDB-4gl5: Structure of human placental aromatase complexed with designed in... -

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Basic information

Entry
Database: PDB / ID: 4gl5
TitleStructure of human placental aromatase complexed with designed inhibitor HDDG029 (compound 4)
ComponentsCytochrome P450 19A1
KeywordsOxidoreductase/Oxidoreductase Inhibitor / Oxidoreductase / Estrogen synthetase / Cytochrome P450 reductase / ER membrane / Oxidoreductase-Oxidoreductase Inhibitor complex
Function / homology
Function and homology information


aromatase / Defective CYP19A1 causes AEXS / positive regulation of estradiol secretion / androgen catabolic process / female genitalia development / syncytium formation / negative regulation of chronic inflammatory response / estrogen biosynthetic process / Estrogen biosynthesis / testosterone biosynthetic process ...aromatase / Defective CYP19A1 causes AEXS / positive regulation of estradiol secretion / androgen catabolic process / female genitalia development / syncytium formation / negative regulation of chronic inflammatory response / estrogen biosynthetic process / Estrogen biosynthesis / testosterone biosynthetic process / sterol metabolic process / estrogen 2-hydroxylase activity / prostate gland growth / aromatase activity / negative regulation of macrophage chemotaxis / steroid biosynthetic process / mammary gland development / steroid hydroxylase activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen / female gonad development / uterus development / Endogenous sterols / oxygen binding / response to estradiol / electron transfer activity / iron ion binding / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / membrane
Similarity search - Function
: / Cytochrome P450, E-class, group I / Cytochrome p450 / Cytochrome P450 / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-G29 / PROTOPORPHYRIN IX CONTAINING FE / Aromatase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.48 Å
AuthorsGhosh, D.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Novel aromatase inhibitors by structure-guided design.
Authors: Ghosh, D. / Lo, J. / Morton, D. / Valette, D. / Xi, J. / Griswold, J. / Hubbell, S. / Egbuta, C. / Jiang, W. / An, J. / Davies, H.M.
History
DepositionAug 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 12, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 19, 2012Group: Database references
Revision 1.2Oct 24, 2012Group: Database references
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Cytochrome P450 19A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,9243
Polymers57,9551
Non-polymers9692
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)140.329, 140.329, 118.733
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Cytochrome P450 19A1 / Aromatase / CYPXIX / Cytochrome P-450AROM / Estrogen synthase


Mass: 57954.863 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P11511, unspecific monooxygenase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-G29 / (6alpha,8alpha)-6-(but-2-yn-1-yloxy)androsta-1,4-diene-3,17-dione


Mass: 352.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H28O3

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 5.82 Å3/Da / Density % sol: 78.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.4
Details: The enzyme-inhibitor complexes were prepared by the addition from 20mM stock solutions of compound 4 in PEG550 to 18 M (~1mg/ml) of aromatase, to give a final inhibitor concentration of 300 ...Details: The enzyme-inhibitor complexes were prepared by the addition from 20mM stock solutions of compound 4 in PEG550 to 18 M (~1mg/ml) of aromatase, to give a final inhibitor concentration of 300 uM. The mixture was incubated overnight at 4 C in 100mM potassium phosphate buffer pH 7.4 containing 20% glycerol, 20mM dithiothreitol, 0.5 M ASD and 1mM BDM. The complex was then concentrated to 25-30mg/ml using ultrafiltration. Protein was setup for crystallization using protein to cocktail ratios 2:1 and 3:1. The protein was mixed with reservoir cocktails of 24-30% polyethylene glycol 4000 in 50mM NaCl, 50mM Tris, pH 8.5 and vapor diffused in sealed 24-well sitting drop plates against corresponding reservoir solution., VAPOR DIFFUSION, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 18, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.48→121.53 Å / Num. all: 17289 / Num. obs: 17289 / % possible obs: 91.5 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 1 / Redundancy: 3.8 % / Rmerge(I) obs: 0.154 / Rsym value: 0.154 / Net I/σ(I): 14.1

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Processing

Software
NameVersionClassification
HKL-3000data collection
CCP4model building
REFMAC5.5.0109refinement
HKL-3000data reduction
HKL-3000data scaling
CCP4phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 3.48→50 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.88 / SU B: 21.02 / SU ML: 0.325 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 2.368 / ESU R Free: 0.469 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26036 832 5.2 %RANDOM
Rwork0.21023 ---
obs0.21277 15300 91.19 %-
all-17289 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 91.221 Å2
Baniso -1Baniso -2Baniso -3
1-2.91 Å21.45 Å2-0 Å2
2--2.91 Å2-0 Å2
3----4.36 Å2
Refinement stepCycle: LAST / Resolution: 3.48→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3658 0 69 0 3727
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0223816
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3112.0155162
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2245451
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.13923.576165
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.44815711
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1961525
X-RAY DIFFRACTIONr_chiral_restr0.0940.2565
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212808
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4881.52253
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.92523662
X-RAY DIFFRACTIONr_scbond_it0.87931563
X-RAY DIFFRACTIONr_scangle_it1.5964.51500
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.48→3.571 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 59 -
Rwork0.289 1151 -
obs--94.24 %

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