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- PDB-6bcz: Crystal structure of human CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 6bcz
TitleCrystal structure of human CYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / monooxygenase / inhibitor / 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 / cholesterol metabolic process / xenobiotic 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
Chem-D7Y / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 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: Mol Pharm. / Year: 2018
Title: Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities.
Authors: Samuels, E.R. / Sevrioukova, I.
History
DepositionOct 20, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Author supporting evidence / Database references / Category: citation / pdbx_audit_support
Item: _citation.country / _citation.journal_id_ISSN / _pdbx_audit_support.funding_organization
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 29, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _pdbx_struct_assembly.details / _pdbx_struct_assembly.method_details / _pdbx_struct_assembly.oligomeric_count / _pdbx_struct_assembly.oligomeric_details
Revision 1.4Oct 4, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,7713
Polymers55,7581
Non-polymers1,0132
Water19811
1
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)227,08312
Polymers223,0314
Non-polymers4,0528
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_545-x,-y-1,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_545x,-y-1,-z1
Buried area10260 Å2
ΔGint-134 kcal/mol
Surface area72960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.369, 101.160, 128.090
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / Plasmid: PCWORI / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With NADH or NADPH as one donor, and incorporation of one atom of oxygen ...References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With NADH or NADPH as one donor, and incorporation of one atom of oxygen into the other donor, EC: 1.14.13.157, EC: 1.14.13.32, unspecific monooxygenase, EC: 1.14.13.67, EC: 1.14.13.97
#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-D7Y / tert-butyl (2-{[(2R)-3-oxo-2-[(propan-2-yl)amino]-3-{[(pyridin-3-yl)methyl]amino}propyl]sulfanyl}ethyl)carbamate


Mass: 396.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H32N4O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / Source method: isolated from a natural source / Formula: H2O

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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: 2.25 Å3/Da / Density % sol: 45.27 %
Crystal growTemperature: 283 K / Method: microbatch / pH: 7 / Details: PEG3350, malonate

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Data collection

DiffractionMean temperature: 108 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.23→79.39 Å / Num. obs: 24881 / % possible obs: 99.9 % / Redundancy: 5.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.049 / Rpim(I) all: 0.023 / Net I/σ(I): 11.2
Reflection shellResolution: 2.32→2.35 Å / Redundancy: 5.4 % / Rmerge(I) obs: 1.813 / Num. unique obs: 3582 / CC1/2: 0.3 / Rpim(I) all: 0.858 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VCC

5vcc


Resolution: 2.23→79.388 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 36 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2609 1202 4.83 %
Rwork0.2001 --
obs0.2031 24870 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.23→79.388 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3708 0 70 11 3789
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094010
X-RAY DIFFRACTIONf_angle_d1.2245450
X-RAY DIFFRACTIONf_dihedral_angle_d14.4921551
X-RAY DIFFRACTIONf_chiral_restr0.046598
X-RAY DIFFRACTIONf_plane_restr0.006690
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.23-2.31930.43811500.43282579X-RAY DIFFRACTION100
2.3193-2.42480.39181370.34932570X-RAY DIFFRACTION100
2.4248-2.55270.33981350.28472596X-RAY DIFFRACTION100
2.5527-2.71260.31211230.26392603X-RAY DIFFRACTION100
2.7126-2.92210.29841270.23772633X-RAY DIFFRACTION100
2.9221-3.21610.30761190.24472633X-RAY DIFFRACTION100
3.2161-3.68150.30411360.2262626X-RAY DIFFRACTION100
3.6815-4.63820.24141430.17892638X-RAY DIFFRACTION100
4.6382-79.43810.22461320.16762790X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -19.366 Å / Origin y: -27.127 Å / Origin z: -13.0568 Å
111213212223313233
T0.4593 Å2-0.0582 Å2-0.0349 Å2-0.6208 Å20.0655 Å2--0.5078 Å2
L3.5119 °2-2.6892 °20.8549 °2-6.4055 °2-1.3566 °2--2.878 °2
S-0.0017 Å °0.2084 Å °0.2273 Å °0.2767 Å °-0.1063 Å °-0.0123 Å °-0.2989 Å °0.1677 Å °0.105 Å °
Refinement TLS groupSelection details: all

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