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- PDB-7uay: Crystal structure of human CYP3A4 with the caged inhibitor -

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Basic information

Entry
Database: PDB / ID: 7uay
TitleCrystal structure of human CYP3A4 with the caged inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/INHIBITOR / CYP3A4 / inhibitor / complex / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex / 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-O39 / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.78 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: 2022
Title: Ir(III)-Based Agents for Monitoring the Cytochrome P450 3A4 Active Site Occupancy.
Authors: Denison, M. / Steinke, S.J. / Majeed, A. / Turro, C. / Kocarek, T.A. / Sevrioukova, I.F. / Kodanko, J.J.
History
DepositionMar 14, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 14, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 18, 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)57,3393
Polymers55,7581
Non-polymers1,5822
Water00
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,6796
Polymers111,5162
Non-polymers3,1634
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Unit cell
Length a, b, c (Å)76.940, 99.530, 135.680
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 (E. coli) / Strain (production host): CD41
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-O39 / (N-[([2,2'-bipyridin]-5-yl-kappa~2~N~1~,N~1'~)methyl]-3-{[(pyridin-3-yl)methyl]sulfanyl}propanamide)bis[2-(quinolin-2-yl-kappaN)phenyl-kappaC~1~]iridium


Mass: 965.174 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C50H40IrN6OS / Feature type: SUBJECT OF INVESTIGATION
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: 2.33 Å3/Da / Density % sol: 47.19 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: PEG 3350, sodium malonate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Sep 27, 2020 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.78→80.25 Å / Num. obs: 13434 / % possible obs: 99.8 % / Redundancy: 7.9 % / Biso Wilson estimate: 93 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.038 / Net I/σ(I): 9.6
Reflection shellResolution: 2.78→2.93 Å / Redundancy: 8.2 % / Rmerge(I) obs: 1.988 / Num. unique obs: 1915 / CC1/2: 0.378 / Rpim(I) all: 0.744 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7ksa

7ksa


Resolution: 2.78→49.765 Å / SU ML: 0.52 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 37.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2803 660 4.92 %
Rwork0.2577 --
obs0.2588 13422 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.78→49.765 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3493 0 102 0 3595
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043699
X-RAY DIFFRACTIONf_angle_d1.4885033
X-RAY DIFFRACTIONf_dihedral_angle_d13.3222208
X-RAY DIFFRACTIONf_chiral_restr0.039544
X-RAY DIFFRACTIONf_plane_restr0.004625
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.78-2.99460.45621280.41932520X-RAY DIFFRACTION100
2.9946-3.29590.42491300.34042500X-RAY DIFFRACTION99
3.2959-3.77270.32411390.29782505X-RAY DIFFRACTION100
3.7727-4.75260.2741260.242570X-RAY DIFFRACTION100
4.7526-49.7650.23131370.22752667X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -18.8013 Å / Origin y: -23.9086 Å / Origin z: -15.4429 Å
111213212223313233
T0.524 Å2-0.0177 Å20.1448 Å2-0.6586 Å20.1401 Å2--0.7049 Å2
L4.014 °2-1.2214 °2-0.4731 °2-5.2888 °21.5845 °2--3.1999 °2
S-0.1567 Å °-0.2452 Å °-0.4243 Å °0.0813 Å °-0.2342 Å °-0.2932 Å °0.4679 Å °0.1336 Å °0.3587 Å °
Refinement TLS groupSelection details: all

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