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

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Basic information

Entry
Database: PDB / ID: 8exb
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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity ...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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / lipid hydroxylation / aflatoxin metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / testosterone 6-beta-hydroxylase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / vitamin D metabolic process / steroid catabolic process / Atorvastatin ADME / steroid hydroxylase activity / Xenobiotics / Phase I - Functionalization of compounds / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / unspecific monooxygenase / long-chain fatty acid biosynthetic process / Prednisone ADME / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / cholesterol metabolic process / steroid binding / xenobiotic metabolic process / monooxygenase activity / oxygen binding / lipid metabolic process / 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 / Cytochrome P450 / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450 ...Cytochrome P450, E-class, group II / Cytochrome P450, E-class, CYP3A / : / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-X4E / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 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 25, 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 1.2Sep 20, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _pdbx_initial_refinement_model.type

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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)57,4063
Polymers55,7581
Non-polymers1,6482
Water82946
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,8116
Polymers111,5162
Non-polymers3,2954
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545x,-y-1,-z1
Unit cell
Length a, b, c (Å)77.230, 99.520, 130.560
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-742-

HOH

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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-X4E / {N-[([2,2'-bipyridin]-5-yl-kappa~2~N~1~,N~1'~)methyl]-3-(pyridin-3-yl)propanamide}bis[2-(quinolin-2-yl-kappaN)-1-benzothiophen-3-yl-kappaC~3~]iridium(1+)


Mass: 1031.255 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C53H38IrN6OS2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / 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: 2.25 Å3/Da / Density % sol: 45.32 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: PEG 3350, HEPES, mixture of di-, tri-, tetra- and penta-ethylene glycols

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Data collection

DiffractionMean temperature: 103 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Jul 2, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.05→79.15 Å / Num. obs: 31759 / % possible obs: 99.6 % / Redundancy: 6.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.036 / Net I/σ(I): 9.2
Reflection shellResolution: 2.05→2.16 Å / Rmerge(I) obs: 1.986 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4585 / CC1/2: 0.563 / Rsym value: 0.832

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5vcc

5vcc


Resolution: 2.05→39.87 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 35.4 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2671 1565 4.94 %
Rwork0.2375 --
obs0.239 31701 99.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.05→39.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3562 0 106 46 3714
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0053775
X-RAY DIFFRACTIONf_angle_d1.5545138
X-RAY DIFFRACTIONf_dihedral_angle_d14.9481409
X-RAY DIFFRACTIONf_chiral_restr0.04556
X-RAY DIFFRACTIONf_plane_restr0.005634
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.05-2.120.38421330.36672710X-RAY DIFFRACTION99
2.12-2.190.38291390.35032672X-RAY DIFFRACTION99
2.19-2.280.39121370.32522717X-RAY DIFFRACTION99
2.28-2.380.36581340.28952700X-RAY DIFFRACTION99
2.38-2.510.31531430.28422729X-RAY DIFFRACTION100
2.51-2.670.33291530.27812728X-RAY DIFFRACTION100
2.67-2.870.31631180.28682730X-RAY DIFFRACTION99
2.87-3.160.32131410.2622772X-RAY DIFFRACTION100
3.16-3.620.27751490.24942752X-RAY DIFFRACTION100
3.62-4.560.23851690.20392750X-RAY DIFFRACTION99
4.56-39.870.21751490.20232876X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -19.5253 Å / Origin y: -26.3834 Å / Origin z: -14.2657 Å
111213212223313233
T0.3065 Å2-0.0049 Å2-0.0049 Å2-0.3893 Å20.0021 Å2--0.336 Å2
L1.5488 °2-1.1657 °20.1507 °2-4.3158 °2-0.7831 °2--1.7825 °2
S-0.1303 Å °-0.0496 Å °0.1104 Å °0.3656 Å °0.0468 Å °-0.0995 Å °-0.2157 Å °-0.0693 Å °0.0745 Å °
Refinement TLS groupSelection details: all

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