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

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Basic information

Entry
Database: PDB / ID: 6bdi
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-DEJ / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 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: 2017
Title: Interaction of the rationally designed ritonavir-like inhibitors with human cytochrome P450 3A4: Impact of the side group interplay
Authors: Samuels, E.R. / Sevrioukova, I.F.
History
DepositionOct 23, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 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)56,9003
Polymers55,7581
Non-polymers1,1422
Water181
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,8006
Polymers111,5162
Non-polymers2,2844
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455-x-1,y,-z1
Unit cell
Length a, b, c (Å)77.610, 102.430, 127.760
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-DEJ / tert-butyl [(2S)-1-(1H-indol-3-yl)-3-{[(2R)-3-oxo-2-[(propan-2-yl)amino]-3-{[(pyridin-3-yl)methyl]amino}propyl]sulfanyl}propan-2-yl]carbamate


Mass: 525.706 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H39N5O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.28 Å3/Da / Density % sol: 45.98 %
Crystal growTemperature: 293 K / Method: microbatch / pH: 6.8 / Details: PEG 3350, malonate

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS3 X 1M / Detector: PIXEL / Date: Apr 14, 2017 / Details: Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.57→79.92 Å / Num. obs: 16151 / % possible obs: 97.8 % / Redundancy: 4.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.03 / Net I/σ(I): 9.4
Reflection shellResolution: 2.57→2.71 Å / Redundancy: 4.8 % / Rmerge(I) obs: 1.817 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 2312 / CC1/2: 0.315 / Rpim(I) all: 0.897 / % possible all: 97.6

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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: 2.57→51.215 Å / SU ML: 0.48 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.81 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2447 760 4.71 %
Rwork0.192 --
obs0.1946 16126 97.17 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.57→51.215 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3721 0 80 1 3802
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.014012
X-RAY DIFFRACTIONf_angle_d1.2025449
X-RAY DIFFRACTIONf_dihedral_angle_d14.2262432
X-RAY DIFFRACTIONf_chiral_restr0.054589
X-RAY DIFFRACTIONf_plane_restr0.007684
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.57-2.76840.37291450.29853019X-RAY DIFFRACTION97
2.7684-3.0470.40191370.28633067X-RAY DIFFRACTION98
3.047-3.48780.30661640.25013052X-RAY DIFFRACTION98
3.4878-4.39390.24931560.19283065X-RAY DIFFRACTION97
4.3939-51.22510.20511580.16073163X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: -19.4399 Å / Origin y: -23.6875 Å / Origin z: -13.0325 Å
111213212223313233
T0.5563 Å2-0.022 Å20.0836 Å2-0.6872 Å2-0.0644 Å2--0.6047 Å2
L4.3221 °2-3.0216 °2-1.21 °2-6.786 °21.8192 °2--2.9451 °2
S0.128 Å °0.3711 Å °-0.2157 Å °-0.0514 Å °-0.2238 Å °-0.2283 Å °0.1542 Å °-0.1336 Å °0.1054 Å °
Refinement TLS groupSelection details: all

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