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

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Basic information

Entry
Database: PDB / ID: 7kvn
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 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-X6V / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)113,8946
Polymers111,5162
Non-polymers2,3784
Water1,09961
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3100 Å2
ΔGint-45 kcal/mol
Surface area38370 Å2
Unit cell
Length a, b, c (Å)153.761, 95.610, 93.020
Angle α, β, γ (deg.)90.00, 124.21, 90.00
Int Tables number5
Space group name H-MC121

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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.: 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
#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-X6V / tert-butyl [(2S)-1-(1H-indol-3-yl)-3-{[(2R)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate


Mass: 572.761 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C33H40N4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 61 / 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: 2.54 Å3/Da / Density % sol: 51.48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: PEG 3350, sodium malonate

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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: May 19, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.7→76.93 Å / Num. obs: 28152 / % possible obs: 91.9 % / Redundancy: 4.8 % / CC1/2: 0.97 / Net I/σ(I): 4
Reflection shellResolution: 2.7→2.85 Å / Num. unique obs: 3757 / CC1/2: 0.571

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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: 2.7→40.031 Å / SU ML: 0.47 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 35.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2898 1421 5.09 %
Rwork0.2478 --
obs0.25 27907 90.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7→40.031 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7240 0 168 61 7469
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037630
X-RAY DIFFRACTIONf_angle_d0.56310344
X-RAY DIFFRACTIONf_dihedral_angle_d13.2574593
X-RAY DIFFRACTIONf_chiral_restr0.041132
X-RAY DIFFRACTIONf_plane_restr0.0041299
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.79650.39031190.36232383X-RAY DIFFRACTION82
2.7965-2.90840.36731450.34762507X-RAY DIFFRACTION86
2.9084-3.04070.38191120.32062820X-RAY DIFFRACTION96
3.0407-3.2010.33121460.32412798X-RAY DIFFRACTION96
3.201-3.40150.38361360.32252729X-RAY DIFFRACTION94
3.4015-3.66390.30511470.28782477X-RAY DIFFRACTION85
3.6639-4.03230.35161700.25662642X-RAY DIFFRACTION92
4.0323-4.61510.25241630.21682780X-RAY DIFFRACTION96
4.6151-5.81170.27851220.21572553X-RAY DIFFRACTION86
5.8117-40.0310.2141610.19342797X-RAY DIFFRACTION94
Refinement TLS params.Method: refined / Origin x: 25.1062 Å / Origin y: -25.2353 Å / Origin z: 30.7127 Å
111213212223313233
T0.4339 Å2-0.0334 Å2-0.1654 Å2-0.4621 Å20.042 Å2--0.4897 Å2
L1.0654 °2-0.3479 °20.1752 °2-1.3057 °2-1.1928 °2--3.4412 °2
S-0.0177 Å °-0.193 Å °-0.077 Å °0.2234 Å °-0.0442 Å °-0.0526 Å °-0.0591 Å °0.1875 Å °0.0107 Å °
Refinement TLS groupSelection details: all

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