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- PDB-6unj: Human CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 6unj
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 / 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-QDY / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 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: Bioorg.Med.Chem. / Year: 2020
Title: An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.
Authors: Samuels, E.R. / Sevrioukova, I.F.
History
DepositionOct 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2020Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Revision 1.2Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Mar 4, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.4Oct 11, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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)113,8886
Polymers111,5162
Non-polymers2,3724
Water00
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,8886
Polymers111,5162
Non-polymers2,3724
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
2
B: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,8886
Polymers111,5162
Non-polymers2,3724
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_659-x+1,y,-z+41
3
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,77612
Polymers223,0314
Non-polymers4,7458
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_557-x,y,-z+21
crystal symmetry operation3_454x-1/2,y+1/2,z-11
crystal symmetry operation4_558-x+1/2,y+1/2,-z+31
Buried area8680 Å2
ΔGint-135 kcal/mol
Surface area74890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)152.989, 98.080, 93.429
Angle α, β, γ (deg.)90.000, 124.040, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Cytochrome P450 3A4 / 1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / Albendazole sulfoxidase / CYPIIIA3 ...1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / 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 / Taurochenodeoxycholate 6-alpha-hydroxylase


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 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / 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.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-QDY / tert-butyl [(2R)-1-(naphthalen-1-yl)-3-{[(2S)-1-oxo-3-phenyl-1-{[2-(pyridin-3-yl)ethyl]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate


Mass: 569.757 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H39N3O3S / 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: 2.53 Å3/Da / Density % sol: 51.37 %
Crystal growTemperature: 298 K / Method: microbatch / Details: PEG3350, sodium malonate / PH range: 6.0-7.0

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 18, 2018 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.6→77.57 Å / Num. obs: 32836 / % possible obs: 93.2 % / Redundancy: 6 % / Biso Wilson estimate: 91.46 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.036 / Rrim(I) all: 0.091 / Net I/σ(I): 7.6 / Num. measured all: 196720
Reflection shell

Diffraction-ID: 1 / Redundancy: 6 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.6-2.743.0532914148240.3281.3273.3390.594.6
8.22-77.570.032640810610.9990.0140.03533.291.3

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VCC

5vcc


Resolution: 2.6→47.294 Å / SU ML: 0.57 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 45.1
RfactorNum. reflection% reflection
Rfree0.2878 1622 4.99 %
Rwork0.2529 --
obs0.2548 32518 92.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 339.16 Å2 / Biso mean: 147.5553 Å2 / Biso min: 48.32 Å2
Refinement stepCycle: final / Resolution: 2.6→47.294 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7038 0 168 0 7206
Biso mean--115.34 --
Num. residues----876
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047491
X-RAY DIFFRACTIONf_angle_d0.67410158
X-RAY DIFFRACTIONf_chiral_restr0.0411118
X-RAY DIFFRACTIONf_plane_restr0.0051269
X-RAY DIFFRACTIONf_dihedral_angle_d14.3574510
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.6-2.67650.486970.506258091
2.6765-2.76290.53261190.4949259593
2.7629-2.86170.49421470.4478255193
2.8617-2.97620.44381480.3955254692
2.9762-3.11160.3741260.374245788
3.1116-3.27570.42431280.3462252490
3.2757-3.48080.36911070.3104267595
3.4808-3.74950.37081270.2784268095
3.7495-4.12660.29321240.2577250189
4.1266-4.72330.27431890.2208258595
4.7233-5.9490.24651500.2366262794
5.949-47.2940.23171600.1919257591
Refinement TLS params.Method: refined / Origin x: -27.7675 Å / Origin y: -25.5309 Å / Origin z: 108.6095 Å
111213212223313233
T0.6923 Å2-0.1028 Å2-0.0213 Å2-0.6887 Å20.0912 Å2--0.7293 Å2
L0.7407 °2-0.8275 °20.502 °2-1.6065 °2-1.6892 °2--2.1615 °2
S-0.2122 Å °-0.3257 Å °0.0265 Å °0.8099 Å °0.0782 Å °-0.1748 Å °-0.5343 Å °-0.278 Å °-0.4164 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA29 - 496
2X-RAY DIFFRACTION1allA500 - 700
3X-RAY DIFFRACTION1allB29 - 496
4X-RAY DIFFRACTION1allB500 - 700

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