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

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Basic information

Entry
Database: PDB / ID: 6ung
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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity ...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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / lipid hydroxylation / aflatoxin metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / testosterone 6-beta-hydroxylase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / vitamin D metabolic process / steroid catabolic process / Atorvastatin ADME / steroid hydroxylase activity / Xenobiotics / Phase I - Functionalization of compounds / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / unspecific monooxygenase / long-chain fatty acid biosynthetic process / Prednisone ADME / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / cholesterol metabolic process / steroid binding / xenobiotic metabolic process / monooxygenase activity / oxygen binding / lipid metabolic process / 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-QEP / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 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: 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 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 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 1.2Mar 4, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Oct 11, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9453
Polymers55,7581
Non-polymers1,1872
Water39622
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,8906
Polymers111,5162
Non-polymers2,3744
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455-x-1,y,-z1
2
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,78012
Polymers223,0314
Non-polymers4,7498
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
crystal symmetry operation3_455-x-1,y,-z1
crystal symmetry operation4_555x,-y,-z1
Buried area10950 Å2
ΔGint-151 kcal/mol
Surface area73680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.098, 101.440, 127.189
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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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.: 1
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.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-QEP / tert-butyl [(2S)-1-(naphthalen-1-yl)-3-{[(2R)-3-oxo-2-(phenylamino)-3-{[(pyridin-3-yl)methyl]amino}propyl]sulfanyl}propan-2-yl]carbamate


Mass: 570.745 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H38N4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.17 Å3/Da / Density % sol: 43.21 %
Crystal growTemperature: 298 K / Method: microbatch / Details: PEG 3350, 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: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 28, 2017 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→79.31 Å / Num. obs: 22415 / % possible obs: 99.5 % / Redundancy: 5.4 % / Biso Wilson estimate: 76.59 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.026 / Rrim(I) all: 0.061 / Net I/σ(I): 9.9 / Num. measured all: 121867
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.3-2.4251.6661604532360.3750.8161.8620.999.3
7.27-79.315.10.02540087910.9990.0120.02828.199.5

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Processing

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

5vcc


Resolution: 2.3→65.931 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 34.29
RfactorNum. reflection% reflection
Rfree0.2767 1138 5.09 %
Rwork0.2114 --
obs0.2146 22358 99.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 228.38 Å2 / Biso mean: 112.2395 Å2 / Biso min: 52.72 Å2
Refinement stepCycle: final / Resolution: 2.3→65.931 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3647 0 84 22 3753
Biso mean--95.89 98.22 -
Num. residues----453
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073899
X-RAY DIFFRACTIONf_angle_d0.9215293
X-RAY DIFFRACTIONf_chiral_restr0.049579
X-RAY DIFFRACTIONf_plane_restr0.006666
X-RAY DIFFRACTIONf_dihedral_angle_d15.152361
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.3-2.40470.38591370.3397261799
2.4047-2.53150.33021430.3212259499
2.5315-2.69010.3071460.2963261899
2.6901-2.89780.35921250.2891264499
2.8978-3.18940.39631570.2793259799
3.1894-3.65090.37331290.2573266299
3.6509-4.59950.26191460.19362684100
4.5995-65.9310.2221550.1719280499
Refinement TLS params.Method: refined / Origin x: -19.1476 Å / Origin y: -23.8188 Å / Origin z: -12.9117 Å
111213212223313233
T0.5587 Å2-0.0454 Å20.0329 Å2-0.6846 Å2-0.0985 Å2--0.6482 Å2
L2.9721 °2-2.1516 °2-0.8753 °2-6.0249 °21.0168 °2--3.1832 °2
S-0.0161 Å °0.3439 Å °-0.2741 Å °0.3785 Å °-0.1708 Å °0.0161 Å °0.3793 Å °-0.1548 Å °0.1525 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA28 - 496
2X-RAY DIFFRACTION1allA500 - 700
3X-RAY DIFFRACTION1allS1 - 22

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