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

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Basic information

Entry
Database: PDB / ID: 7kvk
TitleHuman CYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4CYP3A4
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 / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinol metabolic process / retinoic acid metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid hydroxylase activity / 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-X7J / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 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)114,02211
Polymers111,2832
Non-polymers2,7399
Water25214
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4030 Å2
ΔGint-65 kcal/mol
Surface area38980 Å2
Unit cell
Length a, b, c (Å)152.591, 98.501, 127.120
Angle α, β, γ (deg.)90.00, 142.59, 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 / CYP3A4 / 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: 55641.609 Da / Num. of mol.: 2 / Mutation: K421A, K424A
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 , 6 types, 23 molecules

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


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-X7J / tert-butyl [(2R)-1-{[(2R)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate


Mass: 533.725 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H39N3O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 14 / Source method: isolated from a natural source / Formula: H2O

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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: 2.81 Å3/Da / Density % sol: 56.24 %
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: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Oct 18, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.55→77.8 Å / Num. obs: 37311 / % possible obs: 99.8 % / Redundancy: 4.3 % / CC1/2: 0.999 / Net I/σ(I): 8.4
Reflection shellResolution: 2.55→2.69 Å / Num. unique obs: 5430 / CC1/2: 0.398

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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: 2.55→63.431 Å / SU ML: 0.43 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 33.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2763 1959 5.26 %
Rwork0.2371 --
obs0.2392 37249 99.64 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.55→63.431 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7254 0 188 14 7456
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027668
X-RAY DIFFRACTIONf_angle_d0.46810397
X-RAY DIFFRACTIONf_dihedral_angle_d12.4994625
X-RAY DIFFRACTIONf_chiral_restr0.0381138
X-RAY DIFFRACTIONf_plane_restr0.0041305
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.55-2.61380.37911130.35172512X-RAY DIFFRACTION99
2.6138-2.68450.37221330.35392510X-RAY DIFFRACTION99
2.6845-2.76350.41091490.35112535X-RAY DIFFRACTION100
2.7635-2.85270.40151440.33512454X-RAY DIFFRACTION100
2.8527-2.95460.37871430.32942524X-RAY DIFFRACTION100
2.9546-3.07290.36991420.31382526X-RAY DIFFRACTION100
3.0729-3.21280.33051440.2852507X-RAY DIFFRACTION100
3.2128-3.38210.26951120.28012546X-RAY DIFFRACTION100
3.3821-3.5940.30691310.26592510X-RAY DIFFRACTION100
3.594-3.87150.28371640.24612490X-RAY DIFFRACTION100
3.8715-4.2610.27851680.21562506X-RAY DIFFRACTION100
4.261-4.87740.24141330.20422546X-RAY DIFFRACTION100
4.8774-6.14420.25061420.21962534X-RAY DIFFRACTION100
6.1442-63.4310.22311410.19072590X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -24.9142 Å / Origin y: -24.6468 Å / Origin z: 30.4763 Å
111213212223313233
T0.5578 Å20.0177 Å20.1048 Å2-0.5352 Å20.0032 Å2--0.6673 Å2
L1.1641 °2-0.4152 °2-0.3318 °2-1.3857 °21.5214 °2--3.106 °2
S-0.1658 Å °-0.4229 Å °-0.0577 Å °0.5183 Å °0.0915 Å °0.0243 Å °0.5831 Å °0.261 Å °0.0645 Å °
Refinement TLS groupSelection details: all

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