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- PDB-5vc0: Crystal structure of human CYP3A4 bound to ritonavir -

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Basic information

Entry
Database: PDB / ID: 5vc0
TitleCrystal structure of human CYP3A4 bound to ritonavir
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/INHIBITOR / cytochrome P450 / CYP3A4 / monooxygenase / ritonavir / inhibitor / 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 / aflatoxin metabolic process / caffeine oxidase activity / lipid hydroxylation / testosterone 6-beta-hydroxylase activity / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / estrogen 16-alpha-hydroxylase activity / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / vitamin D metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / steroid catabolic process / Atorvastatin ADME / steroid hydroxylase activity / Xenobiotics / 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 / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / steroid binding / xenobiotic metabolic process / cholesterol 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
RITONAVIR / PROTOPORPHYRIN IX CONTAINING FE / RITONAVIR / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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: Biochemistry / Year: 2017
Title: High-Level Production and Properties of the Cysteine-Depleted Cytochrome P450 3A4.
Authors: Sevrioukova, I.F.
History
DepositionMar 30, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2017Group: Structure summary / Category: pdbx_molecule_features
Revision 1.2Jun 21, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Jun 28, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.6Oct 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)57,0953
Polymers55,7581
Non-polymers1,3372
Water00
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,1906
Polymers111,5162
Non-polymers2,6754
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_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)228,38112
Polymers223,0314
Non-polymers5,3508
Water0
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 area17230 Å2
ΔGint-217 kcal/mol
Surface area73780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.579, 100.069, 125.220
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 / Mutation: residue 3-22 deletion, C-terminal 4-histidine tag
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, EC: 1.14.13.157, EC: 1.14.13.32, EC: 1.14.13.67, kynurenine 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-RIT / RITONAVIR / A-84538


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 720.944 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H48N6O5S2 / References: RITONAVIR / Comment: medication, antiretroviral*YM
Sequence detailsMET ALA are the first two residues, the fragment 3-22 was deleted

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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: 2.15 Å3/Da / Density % sol: 42.82 %
Crystal growTemperature: 298 K / Method: microbatch / pH: 7.4 / Details: Hampton PegIon2 solution #15

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Data collection

DiffractionMean temperature: 107 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 17, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.7→78.17 Å / Num. obs: 13476 / % possible obs: 99.5 % / Redundancy: 6.1 % / CC1/2: 0.996 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.042 / Net I/av σ(I): 9.1 / Net I/σ(I): 9.1
Reflection shellResolution: 2.7→2.85 Å / Redundancy: 6 % / Rmerge(I) obs: 1.798 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 1938 / CC1/2: 0.34 / Rpim(I) all: 0.79 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4k9w

4k9w


Resolution: 2.7→78.17 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.918 / SU B: 44.67 / SU ML: 0.404 / Cross valid method: THROUGHOUT / ESU R Free: 0.427 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.28327 671 5 %RANDOM
Rwork0.20815 ---
obs0.21183 12781 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 132.665 Å2
Baniso -1Baniso -2Baniso -3
1-0.68 Å20 Å2-0 Å2
2---0.41 Å2-0 Å2
3----0.28 Å2
Refinement stepCycle: 1 / Resolution: 2.7→78.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3731 0 93 0 3824
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0193925
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1892.0155322
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8815461
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.10123.865163
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.83715701
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1891522
X-RAY DIFFRACTIONr_chiral_restr0.0850.2583
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212927
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.0847.0751850
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.91610.6092309
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.3967.3442073
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined10.00460.1036079
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.468 49 -
Rwork0.323 933 -
obs--99.19 %
Refinement TLS params.Method: refined / Origin x: -19.0711 Å / Origin y: -24.0067 Å / Origin z: -12.1705 Å
111213212223313233
T0.1589 Å2-0.0228 Å20.015 Å2-0.0932 Å2-0.0435 Å2--0.0728 Å2
L1.911 °2-0.9184 °2-0.4995 °2-4.6888 °20.6917 °2--2.1702 °2
S-0.1248 Å °0.0729 Å °-0.3399 Å °0.4511 Å °0.0132 Å °0.0662 Å °0.3294 Å °-0.1033 Å °0.1116 Å °

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