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

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Basic information

Entry
Database: PDB / ID: 6daa
TitleHuman CYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / 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
Chem-G0M / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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: Biochemistry / Year: 2019
Title: Structure-Activity Relationships of Rationally Designed Ritonavir Analogues: Impact of Side-Group Stereochemistry, Headgroup Spacing, and Backbone Composition on the Interaction with CYP3A4.
Authors: Samuels, E.R. / Sevrioukova, I.
History
DepositionMay 1, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jun 12, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation_author.identifier_ORCID
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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

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Assembly

Deposited unit
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8803
Polymers55,7581
Non-polymers1,1222
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)76.329, 101.920, 126.220
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-718-

HOH

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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 / Fragment: residues 23-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Production host: Escherichia coli (E. coli)
References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one ...References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor, 1,8-cineole 2-exo-monooxygenase, 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-G0M / tert-butyl [(2S)-1-{[(2R)-1-oxo-3-phenyl-1-{[(pyridin-3-yl)methyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate


Mass: 505.672 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H35N3O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.22 Å3/Da / Density % sol: 44.53 %
Crystal growTemperature: 293 K / Method: microbatch / Details: peg 3350, sodium malonate

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Nov 19, 2017 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.15→79.3 Å / Num. obs: 26721 / % possible obs: 98.8 % / Redundancy: 4.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.03 / Net I/σ(I): 8.7
Reflection shellResolution: 2.15→2.27 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.941 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 3884 / CC1/2: 0.3 / Rpim(I) all: 1.018 / % possible all: 99.1

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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: 2.15→61.095 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 35.88 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2581 1294 4.94 %
Rwork0.2086 --
obs0.211 26196 96.38 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.15→61.095 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3620 0 79 20 3719
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093825
X-RAY DIFFRACTIONf_angle_d1.0895194
X-RAY DIFFRACTIONf_dihedral_angle_d13.9892319
X-RAY DIFFRACTIONf_chiral_restr0.054574
X-RAY DIFFRACTIONf_plane_restr0.007651
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.23610.44191260.42982574X-RAY DIFFRACTION90
2.2361-2.33790.43191470.42582537X-RAY DIFFRACTION91
2.3379-2.46110.33661410.29422815X-RAY DIFFRACTION99
2.4611-2.61530.32151480.26122791X-RAY DIFFRACTION99
2.6153-2.81730.33211520.26212780X-RAY DIFFRACTION98
2.8173-3.10080.31961500.24522824X-RAY DIFFRACTION99
3.1008-3.54940.30641340.23192842X-RAY DIFFRACTION99
3.5494-4.47170.2371530.19772852X-RAY DIFFRACTION98
4.4717-61.11980.2231430.17352887X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: -18.9293 Å / Origin y: -23.6117 Å / Origin z: -12.8788 Å
111213212223313233
T0.5666 Å2-0.01 Å20.0108 Å2-0.6608 Å2-0.1129 Å2--0.5985 Å2
L3.4426 °2-2.4217 °2-0.7174 °2-5.9857 °20.7935 °2--2.5769 °2
S-0.0347 Å °0.3239 Å °-0.3135 Å °0.2217 Å °-0.0343 Å °-0.0833 Å °0.3897 Å °0.0684 Å °0.0291 Å °
Refinement TLS groupSelection details: all

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