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- PDB-4wnu: Human Cytochrome P450 2D6 Quinidine Complex -

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Basic information

Entry
Database: PDB / ID: 4wnu
TitleHuman Cytochrome P450 2D6 Quinidine Complex
ComponentsCytochrome P450 2D6CYP2D6
Keywordsoxidoreductase/oxidoreductase inhibitor / CYP2D6 / P450 2D6 / Cytochrome P450 / MONOOXYGENASE / oxidoreductase-oxidoreductase inhibitor complex
Function / homology
Function and homology information


negative regulation of cellular organofluorine metabolic process / Miscellaneous substrates / negative regulation of binding / 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 / arachidonic acid metabolic process / alkaloid catabolic process ...negative regulation of cellular organofluorine metabolic process / Miscellaneous substrates / negative regulation of binding / 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 / arachidonic acid metabolic process / alkaloid catabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid metabolic process / : / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / Xenobiotics / oxidative demethylation / 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 / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinol metabolic 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Quinidine / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.26 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 / pdbx_struct_conn_angle / refine_hist / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_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 / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _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.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_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_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
C: Cytochrome P450 2D6
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)220,24631
Polymers214,9224
Non-polymers5,32427
Water12,052669
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,24910
Polymers53,7311
Non-polymers1,5189
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9076
Polymers53,7311
Non-polymers1,1775
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9997
Polymers53,7311
Non-polymers1,2696
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,0918
Polymers53,7311
Non-polymers1,3617
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.340, 192.114, 250.749
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Detailsmonomeric

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Cytochrome P450 2D6 / CYP2D6 / CYPIID6 / Cytochrome P450-DB1 / Debrisoquine 4-hydroxylase


Mass: 53730.566 Da / Num. of mol.: 4 / 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

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Non-polymers , 6 types, 696 molecules

#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-QDN / Quinidine / (9S)-6'-methoxycinchonan-9-ol / Quinidine


Mass: 324.417 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H24N2O2 / Comment: antiarrhythmic*YM
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 669 / Source method: isolated from a natural source / Formula: H2O

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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: 3.21 Å3/Da / Density % sol: 61.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. Quinidine ...Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. Quinidine was added to the mother liquor after crystallization of the P450 2D6 thiordidazine complex.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.097173 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 25, 2011 / 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: 1.097173 Å / Relative weight: 1
ReflectionResolution: 2.26→38.72 Å / Num. obs: 128917 / % possible obs: 98.7 % / Redundancy: 4.2 % / Biso Wilson estimate: 35.66 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.056 / Rpim(I) all: 0.032 / Net I/σ(I): 17.3 / Num. measured all: 535220
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.26-2.34.30.39142752164180.9210.21499.8
12.38-38.723.50.0435.330818790.9960.02694.3

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Processing

Software
NameVersionClassification
PHENIXrefinement
Aimless0.2.17data scaling
PDB_EXTRACT3.15data extraction
RefinementStarting model: 3TBG

3tbg


Resolution: 2.26→38.038 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.05 / Phase error: 24.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2318 6489 5.04 %Random Selection
Rwork0.1897 122265 --
obs0.1918 128754 98.4 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 145.31 Å2 / Biso mean: 49.8595 Å2 / Biso min: 17.48 Å2
Refinement stepCycle: final / Resolution: 2.26→38.038 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14289 0 349 669 15307
Biso mean--39.22 48.65 -
Num. residues----1804
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00815059
X-RAY DIFFRACTIONf_angle_d1.0520484
X-RAY DIFFRACTIONf_chiral_restr0.0392211
X-RAY DIFFRACTIONf_plane_restr0.0052702
X-RAY DIFFRACTIONf_dihedral_angle_d14.8795574
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.26-2.28570.29281980.24641204318100
2.2857-2.31260.282270.229540254252100
2.3126-2.34080.26752010.213640664267100
2.3408-2.37040.22382340.205140684302100
2.3704-2.40160.24212240.218941044328100
2.4016-2.43450.27062090.213840534262100
2.4345-2.46930.25852350.2174056429199
2.4693-2.50610.2572350.221641044339100
2.5061-2.54530.24772140.21934002421699
2.5453-2.5870.28182110.20941264337100
2.587-2.63160.25122500.21394038428899
2.6316-2.67940.24832160.20763996421299
2.6794-2.73090.24811900.2074162435299
2.7309-2.78670.29742330.20633976420999
2.7867-2.84720.22492070.20624083429099
2.8472-2.91340.23572260.20614010423698
2.9134-2.98630.27362040.20964071427598
2.9863-3.0670.27792170.2144034425198
3.067-3.15720.25241950.2094054424998
3.1572-3.2590.26032060.19774025423197
3.259-3.37550.23932330.1994053428697
3.3755-3.51050.25242030.1963947415097
3.5105-3.67020.22532290.18764007423697
3.6702-3.86350.2322270.17924022424996
3.8635-4.10530.20832110.16964028423996
4.1053-4.42180.18252140.16084059427397
4.4218-4.8660.18242160.14454096431297
4.866-5.56820.21142060.16934181438799
5.5682-7.00820.23521960.189443154511100
7.0082-38.04330.19882220.17654384460697

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