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- PDB-5vcg: Crystal structure of the cysteine depleted CYP3A4 bound to bromoe... -

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Basic information

Entry
Database: PDB / ID: 5vcg
TitleCrystal structure of the cysteine depleted CYP3A4 bound to bromoergocryptine
ComponentsCytochrome P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE/SUBSTRATE / cytochrome P450 / CYP3A4 / monooxygenase / cysteine mutation / bromoergocryprine / OXIDOREDUCTASE-SUBSTRATE 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 / alkaloid catabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / : / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / vitamin D metabolic process / Atorvastatin ADME / steroid catabolic process / Xenobiotics / oxidative demethylation / steroid hydroxylase activity / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinoic acid metabolic process / retinol metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / cholesterol metabolic process / steroid binding / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
bromoergocryptine / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 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 1.2Jun 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 1.3Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / 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)57,3117
Polymers55,6721
Non-polymers1,6396
Water1,35175
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,62214
Polymers111,3432
Non-polymers3,27912
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
Buried area3470 Å2
ΔGint-57 kcal/mol
Surface area38740 Å2
MethodPISA
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)229,24428
Polymers222,6864
Non-polymers6,55824
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 area10130 Å2
ΔGint-144 kcal/mol
Surface area74300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.539, 100.459, 133.679
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-749-

HOH

21A-768-

HOH

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Components

#1: Protein Cytochrome P450 3A4 / CYP3A4 / 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: 55671.570 Da / Num. of mol.: 1
Mutation: 3-22 fragment deleted; C58A; C64M; C98A; C239T; C377A; C468S; C-terminal 4-His 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 / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-08Y / bromoergocryptine / bromocriptine / Bromocriptine


Mass: 654.594 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H40BrN5O5 / Comment: agonist*YM
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 75 / Source method: isolated from a natural source / Formula: H2O
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: 2.31 Å3/Da / Density % sol: 46.83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: PEG4000

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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 6M / Detector: PIXEL / Date: Dec 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.2→80.31 Å / Num. obs: 25847 / % possible obs: 97.8 % / Redundancy: 4.4 % / CC1/2: 0.976 / Rmerge(I) obs: 0.199 / Rpim(I) all: 0.099 / Net I/σ(I): 2.9
Reflection shellResolution: 2.2→2.32 Å / Redundancy: 4.5 % / Rmerge(I) obs: 1.811 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 3783 / CC1/2: 0.472 / Rpim(I) all: 0.936 / % possible all: 99.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VCC

5vcc


Resolution: 2.2→80.31 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.911 / SU B: 25.494 / SU ML: 0.27 / Cross valid method: THROUGHOUT / ESU R: 0.357 / ESU R Free: 0.247 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.27227 1297 5.1 %RANDOM
Rwork0.23498 ---
obs0.23693 24305 96.41 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 80.001 Å2
Baniso -1Baniso -2Baniso -3
1-1.7 Å20 Å2-0 Å2
2---1.89 Å20 Å2
3---0.19 Å2
Refinement stepCycle: 1 / Resolution: 2.2→80.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3714 0 110 75 3899
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193932
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3382.0215338
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.445460
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.32423.865163
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.50115695
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.241522
X-RAY DIFFRACTIONr_chiral_restr0.0960.2592
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212899
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_it3.0616.0071843
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.828.9812299
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.4216.4372087
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined10.52351.3966046
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: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 101 -
Rwork0.379 1792 -
obs--97.48 %
Refinement TLS params.Method: refined / Origin x: -18.8464 Å / Origin y: -23.8641 Å / Origin z: -14.3648 Å
111213212223313233
T0.0315 Å2-0.0151 Å20.0555 Å2-0.0615 Å2-0.0238 Å2--0.1358 Å2
L1.1562 °2-1.295 °2-0.4684 °2-2.6172 °20.413 °2--0.8716 °2
S-0.0856 Å °0.0773 Å °-0.0244 Å °0.1484 Å °-0.1 Å °-0.0086 Å °0.1024 Å °0.0949 Å °0.1856 Å °

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