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- PDB-2v0m: Crystal structure of human P450 3A4 in complex with ketoconazole -

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Basic information

Entry
Database: PDB / ID: 2v0m
TitleCrystal structure of human P450 3A4 in complex with ketoconazole
ComponentsCYTOCHROME P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE / METAL-BINDING / TRANSMEMBRANE / ENDOPLASMIC RETICULUM / DRUG METABOLIZING ENZYME / KETOCONAZOL / POLYMORPHISM / MONOOXYGENASE / P450 / NADP / IRON / HEME / CYP3A4 / MEMBRANE / MICROSOME
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
PROTOPORPHYRIN IX CONTAINING FE / Chem-KLN / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSjogren, T. / Ekroos, M.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2006
Title: Structural Basis for Ligand Promiscuity in Cytochrome P450 3A4
Authors: Ekroos, M. / Sjogren, T.
History
DepositionMay 15, 2007Deposition site: PDBE / Processing site: PDBE
SupersessionJun 26, 2007ID: 2J0C
Revision 1.0Jun 26, 2007Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2011Group: Database references / Other ...Database references / Other / Refinement description / Version format compliance
Revision 1.2May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CYTOCHROME P450 3A4
B: CYTOCHROME P450 3A4
C: CYTOCHROME P450 3A4
D: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,64316
Polymers221,9264
Non-polymers6,71712
Water0
1
A: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1614
Polymers55,4811
Non-polymers1,6793
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1614
Polymers55,4811
Non-polymers1,6793
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
3
C: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1614
Polymers55,4811
Non-polymers1,6793
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
4
D: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1614
Polymers55,4811
Non-polymers1,6793
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)228.942, 66.363, 146.419
Angle α, β, γ (deg.)90.00, 102.80, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
CYTOCHROME P450 3A4 / CYP3A4 / QUININE 3-MONOOXYGENASE / CYPIIIA4 / NIFEDIPINE OXIDASE / TAUROCHENODEOXYCHOLATE 6-ALPHA- ...QUININE 3-MONOOXYGENASE / CYPIIIA4 / NIFEDIPINE OXIDASE / TAUROCHENODEOXYCHOLATE 6-ALPHA- HYDROXYLASE / NF-25 / P450-PCN1


Mass: 55481.480 Da / Num. of mol.: 4 / Fragment: SOLUBLE DOMAIN, RESIDUES 24-502
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Organ: LIVER / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): XL1 BLUE
References: UniProt: P08684, unspecific monooxygenase, EC: 1.14.13.67
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-KLN / 1-ACETYL-4-(4-{[(2S,4R)-2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]METHOXY}PHENYL)PIPERAZINE / Levoketoconazole


Mass: 531.431 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C26H28Cl2N4O4 / Comment: inhibitor*YM
Sequence detailsTHE SEQUENCE CONFLICTS CAN BE DERIVED TO A SEQUENCING ERROR IN THE ORIGINAL WORK DESCRIBING THE ...THE SEQUENCE CONFLICTS CAN BE DERIVED TO A SEQUENCING ERROR IN THE ORIGINAL WORK DESCRIBING THE PROTEIN SEQUENCE, REFERENCES ARE GIVEN IN THE UNIPROT ENTRY

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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: 2.5 Å3/Da / Density % sol: 51 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.2
Details: HANGING DROP CRYSTALLISATION USING 1:1 RATIO OF PROTEIN AT 20-27 MG/ML IN A SOLUTION CONTAINING 50 MM POTASSIUM PHOSPHATE PH 7.2, 0.2 MM POTASSIUM CHLORIDE, 20% (V/V) GLYCEROL, 2 MM DITHIOTHREITOL, 1MM EDTA

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.976
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 11, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.8→29.8 Å / Num. obs: 52714 / % possible obs: 98.8 % / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 7.6
Reflection shellResolution: 2.8→2.87 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 5.5 / % possible all: 98.1

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Processing

Software
NameVersionClassification
REFMAC5.2refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1W0E

1w0e


Resolution: 2.8→30 Å / Cor.coef. Fo:Fc: 0.902 / Cor.coef. Fo:Fc free: 0.862 / SU B: 16.124 / SU ML: 0.323 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R Free: 0.432 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflection
Rfree0.271 2654 5.1 %
Rwork0.218 --
obs0.22 49153 97.1 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 31.89 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å20 Å22.01 Å2
2--0.28 Å20 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 2.8→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14650 0 418 0 15068
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.080.02215473
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1752.04221004
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.21751812
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.98523.959634
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.854152733
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9171584
X-RAY DIFFRACTIONr_chiral_restr0.0790.22294
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0211491
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2040.27350
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.310.210702
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1450.2426
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1470.277
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0430.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4021.59435
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.715214965
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.73136848
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.2054.56031
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
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: 2.8→2.87 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.347 179
Rwork0.269 3476

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