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- PDB-8ewn: Crystal structure of CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8ewn
TitleCrystal structure of CYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/INHIBITOR / cytochrome P450 / CYP3A4 / inhibitor / complex / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
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 / steroid hydroxylase activity / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / steroid binding / xenobiotic metabolic process / cholesterol metabolic process / monooxygenase activity / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-X1O / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsSevrioukova, I.F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)ES025767 United States
CitationJournal: Inorg.Chem. / Year: 2023
Title: Dynamic Ir(III) Photosensors for the Major Human Drug-Metabolizing Enzyme Cytochrome P450 3A4.
Authors: Denison, M. / Ahrens, J.J. / Dunbar, M.N. / Warmahaye, H. / Majeed, A. / Turro, C. / Kocarek, T.A. / Sevrioukova, I.F. / Kodanko, J.J.
History
DepositionOct 24, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: 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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,2653
Polymers55,7581
Non-polymers1,5072
Water27015
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,5306
Polymers111,5162
Non-polymers3,0154
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545x,-y-1,-z1
Unit cell
Length a, b, c (Å)75.520, 99.291, 125.399
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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: 55757.812 Da / Num. of mol.: 1 / Mutation: residues 3-22 deleted, C-terminal 4-histidine tag
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): C41
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: isolated from a genetically manipulated source
Formula: C34H32FeN4O4
#3: Chemical ChemComp-X1O / {N-[([2,2'-bipyridin]-5-yl-kappa~2~N~1~,N~1'~)methyl]-3-(pyridin-4-yl)propanamide}bis[3,5-difluoro-2-(pyridin-2-yl-kappaN)phenyl-kappaC~1~]iridium(1+)


Mass: 890.927 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H30F4IrN6O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / 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: 2.11 Å3/Da / Density % sol: 41.65 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: PEG 3350, HEPES, mixture of di, tr-, tetra- and pentaethylene glycols

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Data collection

DiffractionMean temperature: 103 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Jun 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→43.39 Å / Num. obs: 27887 / % possible obs: 100 % / Redundancy: 13 % / CC1/2: 0.999 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.021 / Net I/σ(I): 13.3
Reflection shellResolution: 2.1→2.21 Å / Rmerge(I) obs: 2.363 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 4018 / CC1/2: 0.557 / Rpim(I) all: 0.684

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5vcc

5vcc


Resolution: 2.1→39.39 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 34.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2566 1369 4.95 %
Rwork0.2373 --
obs0.2382 27641 99.11 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→39.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3552 0 96 15 3663
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123751
X-RAY DIFFRACTIONf_angle_d2.2995102
X-RAY DIFFRACTIONf_dihedral_angle_d8.94484
X-RAY DIFFRACTIONf_chiral_restr0.061552
X-RAY DIFFRACTIONf_plane_restr0.011633
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.180.39881280.37322582X-RAY DIFFRACTION100
2.18-2.260.38891310.34382622X-RAY DIFFRACTION100
2.26-2.360.35571570.31472575X-RAY DIFFRACTION99
2.37-2.490.37081160.30792623X-RAY DIFFRACTION99
2.49-2.650.33541450.29252595X-RAY DIFFRACTION99
2.65-2.850.36251470.29762593X-RAY DIFFRACTION98
2.85-3.140.36381350.29842603X-RAY DIFFRACTION98
3.14-3.590.28531320.25632617X-RAY DIFFRACTION98
3.59-4.520.25591370.22122662X-RAY DIFFRACTION99
4.52-39.390.19721410.20242800X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -19.0683 Å / Origin y: -26.4275 Å / Origin z: -12.9934 Å
111213212223313233
T0.6545 Å20.1003 Å20.0091 Å2-0.6947 Å20.0446 Å2--0.5533 Å2
L2.0054 °2-0.8863 °20.5361 °2-4.8073 °2-1.0762 °2--2.3956 °2
S-0.2611 Å °-0.0467 Å °0.2353 Å °0.6197 Å °0.2457 Å °-0.1857 Å °-0.5572 Å °-0.1711 Å °0.0281 Å °
Refinement TLS groupSelection details: all

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