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- PDB-8spd: Cytochrome P450 (CYP) 3A4 crystallized with clotrimazole -

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Basic information

Entry
Database: PDB / ID: 8spd
TitleCytochrome P450 (CYP) 3A4 crystallized with clotrimazole
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE / Inhibitor / complex / CYP / cytochrome P450
Function / homology
Function and homology information


quinine 3-monooxygenase / 1,8-cineole 2-exo-monooxygenase / albendazole monooxygenase (sulfoxide-forming) / quinine 3-monooxygenase activity / 1,8-cineole 2-exo-monooxygenase activity / 1-alpha,25-dihydroxyvitamin D3 23-hydroxylase activity / vitamin D3 25-hydroxylase activity / testosterone 6-beta-hydroxylase activity / vitamin D 24-hydroxylase activity / vitamin D catabolic process ...quinine 3-monooxygenase / 1,8-cineole 2-exo-monooxygenase / albendazole monooxygenase (sulfoxide-forming) / quinine 3-monooxygenase activity / 1,8-cineole 2-exo-monooxygenase activity / 1-alpha,25-dihydroxyvitamin D3 23-hydroxylase activity / vitamin D3 25-hydroxylase activity / testosterone 6-beta-hydroxylase activity / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / aflatoxin metabolic process / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / estrogen 2-hydroxylase activity / lipid hydroxylation / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / vitamin D metabolic process / Atorvastatin ADME / oxidative demethylation / : / steroid catabolic process / Xenobiotics / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinol metabolic process / retinoic acid metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / steroid hydroxylase activity / xenobiotic catabolic process / monooxygenase activity / steroid binding / cholesterol metabolic process / xenobiotic metabolic process / lipid metabolic process / oxygen binding / oxidoreductase activity / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / enzyme binding / cytoplasm
Similarity search - Function
Cytochrome P450, E-class, group II / Cytochrome P450, E-class, CYP3A / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
1-[(2-CHLOROPHENYL)(DIPHENYL)METHYL]-1H-IMIDAZOLE / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsHsu, M.H. / Johnson, E.F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM031001 United States
CitationJournal: Drug Metab.Dispos. / Year: 2023
Title: Differential Effects of Clotrimazole on X-Ray Crystal Structures of Human Cytochromes P450 3A5 and 3A4.
Authors: Hsu, M.H. / Johnson, E.F.
History
DepositionMay 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5563
Polymers55,5951
Non-polymers9612
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.178, 101.792, 125.691
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Space group name HallI22
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z
#4: -x,-y,z
#5: x+1/2,y+1/2,z+1/2
#6: x+1/2,-y+1/2,-z+1/2
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

#1: Protein Cytochrome P450 3A4 / 1 / 4-cineole 2-exo-monooxygenase / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase ...1 / 4-cineole 2-exo-monooxygenase / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase (sulfoxide-forming) / Albendazole sulfoxidase / CYPIIIA3 / CYPIIIA4 / Cholesterol 25-hydroxylase / Cytochrome P450 3A3 / Cytochrome P450 HLp / Cytochrome P450 NF-25 / Cytochrome P450-PCN1 / Nifedipine oxidase / Quinine 3-monooxygenase


Mass: 55594.637 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Plasmid: pSE3A4dH / Production host: Escherichia coli (E. coli) / Strain (production host): DH5alpha
References: UniProt: P08684, unspecific monooxygenase, 1,8-cineole 2-exo-monooxygenase, albendazole monooxygenase (sulfoxide-forming), quinine 3-monooxygenase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL6 / 1-[(2-CHLOROPHENYL)(DIPHENYL)METHYL]-1H-IMIDAZOLE / CLOTRIMAZOLE


Mass: 344.837 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H17ClN2 / Comment: medication, antifungal*YM
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: 2.22 Å3/Da / Density % sol: 44.6 %
Crystal growTemperature: 296 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: PEF 3350, HEPES, lithium sulfate, sodium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-1 / Wavelength: 0.97946 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Nov 7, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2.9→39.55 Å / Num. obs: 21098 / % possible obs: 99.9 % / Redundancy: 11.1 % / Biso Wilson estimate: 114.51 Å2 / CC1/2: 0.999 / Net I/σ(I): 13.5
Reflection shellResolution: 3→3.08 Å / Redundancy: 13.8 % / Mean I/σ(I) obs: 0.9 / Num. unique obs: 1804 / CC1/2: 0.343 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.9→39.55 Å / SU ML: 0.6368 / Cross valid method: FREE R-VALUE / σ(F): 1.91 / Phase error: 36.7469
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Details: Anomalous Pairs |F(+)| and |F(-)| were used separately for refinement numbering 21098.
RfactorNum. reflection% reflectionSelection details
Rfree0.2694 1042 4.94 %Random selection
Rwork0.2215 20056 --
obs0.224 21098 99.5 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 130.25 Å2
Refinement stepCycle: LAST / Resolution: 2.9→39.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3454 0 68 0 3522
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00213613
X-RAY DIFFRACTIONf_angle_d0.52574935
X-RAY DIFFRACTIONf_chiral_restr0.0398562
X-RAY DIFFRACTIONf_plane_restr0.0036652
X-RAY DIFFRACTIONf_dihedral_angle_d9.28011334
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.050.42181680.40912763X-RAY DIFFRACTION97.02
3.05-3.240.36641380.34632882X-RAY DIFFRACTION99.93
3.24-3.490.38111460.30032886X-RAY DIFFRACTION99.97
3.49-3.850.29031400.27382882X-RAY DIFFRACTION100
3.85-4.40.27811390.22592900X-RAY DIFFRACTION99.93
4.4-5.540.21211470.20912877X-RAY DIFFRACTION99.9
5.54-39.550.25511640.17422866X-RAY DIFFRACTION99.77
Refinement TLS params.Method: refined / Origin x: 19.068 Å / Origin y: 27.274 Å / Origin z: 13.276 Å
111213212223313233
T0.847329638102 Å20.0898503394844 Å2-0.0163065968161 Å2-0.944190138756 Å20.00215705269496 Å2--0.644692867463 Å2
L3.37227642636 °21.2624315148 °20.384408874004 °2-5.57005171335 °2-0.239208465426 °2--2.96366974226 °2
S0.0466542689015 Å °-0.174807340272 Å °-0.193291563998 Å °-0.562545583053 Å °-0.0257721522147 Å °0.050843871324 Å °0.490664621069 Å °0.316580591922 Å °-0.0161125483422 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 28:496 OR RESID 601:602 ) )A28 - 496
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 28:496 OR RESID 601:602 ) )A601 - 602

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