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- PDB-4wnw: Human Cytochrome P450 2D6 Thioridazine Complex -

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Basic information

Entry
Database: PDB / ID: 4wnw
TitleHuman Cytochrome P450 2D6 Thioridazine Complex
ComponentsCytochrome P450 2D6
Keywordsoxidoreductase/oxidoreductase inhibitor / CYP2D6 / P450 2D6 / P450 / MONOOXYGENASE / oxidoreductase-oxidoreductase inhibitor complex
Function / homology
Function and homology information


negative regulation of organofluorine metabolic process / Miscellaneous substrates / isoquinoline alkaloid metabolic process / Fatty acids / coumarin metabolic process / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor / CYP2E1 reactions / arachidonate metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity ...negative regulation of organofluorine metabolic process / Miscellaneous substrates / isoquinoline alkaloid metabolic process / Fatty acids / coumarin metabolic process / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor / CYP2E1 reactions / arachidonate metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid metabolic process / alkaloid catabolic process / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / oxidative demethylation / Xenobiotics / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen / retinol metabolic process / estrogen metabolic process / long-chain fatty acid biosynthetic process / Aspirin ADME / steroid metabolic process / xenobiotic catabolic process / cholesterol metabolic process / xenobiotic metabolic process / monooxygenase activity / oxidoreductase activity / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / mitochondrion / cytoplasm
Similarity search - Function
Cytochrome P450, E-class, group I, CYP2D-like / : / Cytochrome P450, E-class, group I / 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 I, CYP2D-like / : / Cytochrome P450, E-class, group I / 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 / NICKEL (II) ION / Chem-RTZ / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.299 Å
AuthorsWang, A. / Stout, C.D. / Johnson, E.F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM031001 United States
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Contributions of Ionic Interactions and Protein Dynamics to Cytochrome P450 2D6 (CYP2D6) Substrate and Inhibitor Binding.
Authors: Wang, A. / Stout, C.D. / Zhang, Q. / Johnson, E.F.
History
DepositionOct 14, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 14, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2Mar 4, 2015Group: Database references
Revision 1.3Sep 13, 2017Group: Author supporting evidence / Database references ...Author supporting evidence / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _software.name
Revision 1.4Nov 22, 2017Group: Refinement description / Category: software / Item: _software.classification
Revision 1.5Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.6Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / refine_hist / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_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_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 2D6
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)109,5409
Polymers107,4612
Non-polymers2,0797
Water00
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7414
Polymers53,7311
Non-polymers1,0103
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7995
Polymers53,7311
Non-polymers1,0694
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)194.190, 55.349, 145.223
Angle α, β, γ (deg.)90.000, 134.190, 90.000
Int Tables number5
Space group name H-MC121
Detailsmonomeric

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Components

#1: Protein Cytochrome P450 2D6 / CYPIID6 / Cytochrome P450-DB1 / Debrisoquine 4-hydroxylase


Mass: 53730.566 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 34-497
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2D6, CYP2DL1 / Plasmid: PCWORI / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): DH5ALPHA / References: UniProt: P10635, unspecific monooxygenase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-RTZ / 10-{2-[(2R)-1-methylpiperidin-2-yl]ethyl}-2-(methylsulfanyl)-10H-phenothiazine


Mass: 370.575 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H26N2S2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni

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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: 2.6 Å3/Da / Density % sol: 52.76 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: PEG-3350,ammonium sulphate,sodium cacodylate,potassium phosphate,NaCl,glycerol,beta-mercaptoethanol,prinomastat,HEGA-10,CHAPS

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.97964 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 12, 2009 / Details: Rh coated flat mirror
RadiationMonochromator: Side scattering bent cube-root I-beam single crystal
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97964 Å / Relative weight: 1
ReflectionResolution: 3.298→33.102 Å / Num. all: 16994 / Num. obs: 16994 / % possible obs: 99.6 % / Redundancy: 3.7 % / Biso Wilson estimate: 74.75 Å2 / Rpim(I) all: 0.066 / Rrim(I) all: 0.128 / Rsym value: 0.109 / Net I/av σ(I): 6.7 / Net I/σ(I): 11.5 / Num. measured all: 62718
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
3.3-3.483.70.4911.5898924460.2970.4912.798.4
3.48-3.693.80.3142.4878123350.1880.3144.399.9
3.69-3.943.70.2053.7816421840.1230.2056.5100
3.94-4.263.70.1285.9766820520.0780.12810100
4.26-4.663.70.0918.3699818810.0550.09113.599.9
4.66-5.213.70.0819.3630117000.0490.08115.199.8
5.21-6.023.70.0957.9568015390.0580.09512.999.9
6.02-7.373.60.0789.7464512810.0480.07815.899.8
7.37-10.433.50.03320.2355510080.0210.03330.699.3
10.43-33.1023.40.02625.519375680.0160.02638.396.8

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Processing

Software
NameVersionClassification
PHENIXrefinement
SCALA3.3.16data scaling
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3QM4

3qm4


Resolution: 3.299→32.978 Å / SU ML: 0.5 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 29.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2868 1648 5.08 %Random selection
Rwork0.2423 30807 --
obs0.2445 32455 99.39 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 121.36 Å2 / Biso mean: 64.3586 Å2 / Biso min: 28.3 Å2
Refinement stepCycle: final / Resolution: 3.299→32.978 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7236 0 189 0 7425
Biso mean--48.37 --
Num. residues----913
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037649
X-RAY DIFFRACTIONf_angle_d0.88410434
X-RAY DIFFRACTIONf_chiral_restr0.0331119
X-RAY DIFFRACTIONf_plane_restr0.0071418
X-RAY DIFFRACTIONf_dihedral_angle_d15.1172861
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.299-3.3960.34251400.3022508264897
3.396-3.50550.36321180.295825882706100
3.5055-3.63070.32641300.275325892719100
3.6307-3.77580.36091140.280125762690100
3.7758-3.94740.30141360.259826062742100
3.9474-4.15520.30721340.252825842718100
4.1552-4.41490.33031490.23125492698100
4.4149-4.75490.2461260.228325792705100
4.7549-5.23170.29191240.235825842708100
5.2317-5.98480.33161350.25126032738100
5.9848-7.52540.31511790.233625122691100
7.5254-32.97920.19031630.19332529269299

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