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- PDB-2j0d: Crystal structure of human P450 3A4 in complex with erythromycin -

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Basic information

Entry
Database: PDB / ID: 2j0d
TitleCrystal structure of human P450 3A4 in complex with erythromycin
ComponentsCYTOCHROME P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE / POLYMORPHISM / ERYTHROMYCIN / MONOOXYGENASE / METAL-BINDING / TRANSMEMBRANE / ENDOPLASMIC RETICULUM / DRUG METABOLIZING ENZYME / 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
ERYTHROMYCIN A / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 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
DepositionAug 2, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 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 1.4Dec 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 / struct_conn
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 / _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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,9305
Polymers110,9632
Non-polymers1,9673
Water88349
1
A: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,8323
Polymers55,4811
Non-polymers1,3502
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
2
B: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,0982
Polymers55,4811
Non-polymers6161
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)67.254, 210.706, 161.246
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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.: 2 / 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, EC: 1.14.13.97
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-ERY / ERYTHROMYCIN A / Erythromycin


Mass: 733.927 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H67NO13 / Comment: antibiotic*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 49 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE CONFLICT CONFLICT HAS BEEN DESRCRIBED BY GONZALEZ ET AL., DNA VOL: 7, PAGES 79-86, 1998

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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: 2.7 Å3/Da / Density % sol: 53 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.5
Details: HANGING DROP CRYSTALLISATION USING 1:1 RATIO OF PROTEIN AT 20-27 MG/ML AGAINST 0.1 M HEPES PH 7-7.5, 0.2 M LITHIUM SULFATE,0.8-1.0 M LITHIUM CHLORIDE AND 30% PEG4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.939
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 19, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.939 Å / Relative weight: 1
ReflectionResolution: 2.75→29.8 Å / Num. obs: 30291 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 7.2 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 16.4
Reflection shellResolution: 2.75→2.82 Å / Redundancy: 7.4 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 3.9 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1W0E

1w0e


Resolution: 2.75→30 Å / Cor.coef. Fo:Fc: 0.911 / Cor.coef. Fo:Fc free: 0.853 / SU B: 15.723 / SU ML: 0.331 / Cross valid method: THROUGHOUT / ESU R Free: 0.455 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.315 1483 5 %RANDOM
Rwork0.238 ---
obs0.242 27971 97.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Refinement stepCycle: LAST / Resolution: 2.75→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7140 0 137 49 7326
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0237462
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3322.03110123
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8355881
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.89923.775302
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.009151334
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.9351541
X-RAY DIFFRACTIONr_chiral_restr0.0890.21128
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025486
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2190.23596
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3130.25133
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2250.2252
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2170.249
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2850.22
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5331.54581
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.96527294
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.14133230
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.8394.52825
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: 2.75→2.82 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.404 94 -
Rwork0.294 1916 -
obs--91.61 %

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