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- PDB-7kvq: Human CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 7kvq
TitleHuman CYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / CYP3A4 / inhibitor / complex / OXIDOREDUCTASE / 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 2-hydroxylase activity / estrogen 16-alpha-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 / oxidative demethylation / steroid catabolic process / Atorvastatin ADME / 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 / unspecific monooxygenase / Prednisone ADME / 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 / 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-X7D / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsSevrioukova, I.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)ES025767 United States
CitationJournal: Int J Mol Sci / Year: 2021
Title: Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength.
Authors: Samuels, E.R. / Sevrioukova, I.F.
History
DepositionNov 28, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_DOI ..._citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 3A4
B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,29111
Polymers111,5162
Non-polymers2,7759
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4080 Å2
ΔGint-44 kcal/mol
Surface area38330 Å2
Unit cell
Length a, b, c (Å)153.861, 97.360, 93.229
Angle α, β, γ (deg.)90.00, 124.32, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 2 molecules AB

#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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Variant: C41 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: P08684, unspecific monooxygenase, 1,8-cineole 2-exo-monooxygenase, albendazole monooxygenase (sulfoxide-forming), quinine 3-monooxygenase

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Non-polymers , 5 types, 9 molecules

#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical ChemComp-X7D / tert-butyl [(2S)-1-(naphthalen-1-yl)-3-{[(2S)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate


Mass: 583.783 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H41N3O3S / Feature type: SUBJECT OF INVESTIGATION

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Details

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: 2.59 Å3/Da / Density % sol: 52.43 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: PEG 4000, HEPES, lithium sulfate

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Sep 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.7→77.28 Å / Num. obs: 30116 / % possible obs: 96.4 % / Redundancy: 5.9 % / CC1/2: 0.999 / Net I/σ(I): 8.5
Reflection shellResolution: 2.7→2.85 Å / Num. unique obs: 4423 / CC1/2: 0.372

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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: 5vcc

5vcc


Resolution: 2.75→63.537 Å / SU ML: 0.48 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 34.59 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2795 1371 4.82 %
Rwork0.2504 --
obs0.2518 28467 96.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.75→63.537 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7256 0 193 0 7449
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027666
X-RAY DIFFRACTIONf_angle_d0.49710384
X-RAY DIFFRACTIONf_dihedral_angle_d12.7474609
X-RAY DIFFRACTIONf_chiral_restr0.0391134
X-RAY DIFFRACTIONf_plane_restr0.0041302
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.75-2.84830.37011310.34452725X-RAY DIFFRACTION97
2.8483-2.96240.3823960.34512735X-RAY DIFFRACTION96
2.9624-3.09720.37811320.33572706X-RAY DIFFRACTION96
3.0972-3.26050.35961120.32312613X-RAY DIFFRACTION92
3.2605-3.46470.32341420.28922737X-RAY DIFFRACTION98
3.4647-3.73220.2971930.27432729X-RAY DIFFRACTION98
3.7322-4.10780.30591490.25312718X-RAY DIFFRACTION97
4.1078-4.7020.2761060.22542641X-RAY DIFFRACTION93
4.702-5.92340.25081550.23732734X-RAY DIFFRACTION97
5.9234-63.5370.23991550.21772758X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: 126.3483 Å / Origin y: 31.8041 Å / Origin z: 107.3724 Å
111213212223313233
T0.4521 Å2-0.0154 Å2-0.0219 Å2-0.4746 Å2-0.0102 Å2--0.438 Å2
L0.5882 °2-0.2415 °20.1035 °2-1.0308 °2-1.0104 °2--1.2833 °2
S-0.086 Å °-0.2191 Å °0.0633 Å °0.2986 Å °0.0142 Å °-0.1256 Å °-0.3811 Å °-0.0619 Å °-0.0016 Å °
Refinement TLS groupSelection details: all

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