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- PDB-4wnv: Human Cytochrome P450 2D6 Quinine Complex -

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Basic information

Entry
Database: PDB / ID: 4wnv
TitleHuman Cytochrome P450 2D6 Quinine 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 binding / negative regulation of cellular 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 / arachidonic acid metabolic process / anandamide 8,9 epoxidase activity ...negative regulation of binding / negative regulation of cellular 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 / arachidonic acid metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / alkaloid metabolic 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 / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinol metabolic process / Aspirin ADME / steroid metabolic process / xenobiotic catabolic process / monooxygenase activity / xenobiotic metabolic process / cholesterol metabolic process / 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 / Quinine / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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 / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_audit_support / pdbx_database_status / pdbx_struct_oper_list
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
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 / 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 / _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)219,83428
Polymers214,9224
Non-polymers4,91224
Water5,332296
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,0528
Polymers53,7311
Non-polymers1,3217
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9447
Polymers53,7311
Non-polymers1,2136
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9867
Polymers53,7311
Non-polymers1,2566
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8526
Polymers53,7311
Non-polymers1,1215
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.569, 192.699, 249.588
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 / 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, 320 molecules

#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-QI9 / Quinine / (3alpha,8alpha,9R)-6'-methoxycinchonan-9-ol


Mass: 324.417 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H24N2O2 / Comment: medication*YM
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 296 / 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: 3.22 Å3/Da / Density % sol: 61.81 %
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. Quinine ...Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. Quinine 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: 2.35→38.74 Å / Num. obs: 114948 / % possible obs: 98.4 % / Redundancy: 3.5 % / Biso Wilson estimate: 25.96 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.037 / Net I/σ(I): 16.8 / Num. measured all: 401591
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
2.35-2.393.60.2256.22079757160.9650.13599.6
12.87-38.743.20.03730.624397640.9960.02592.1

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Processing

Software
NameVersionClassification
Aimless0.2.17data scaling
PHENIX1.9refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TBG

3tbg


Resolution: 2.35→35.426 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 0.01 / Phase error: 25 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2382 11031 5.02 %Random selection
Rwork0.2022 208769 --
obs0.204 109085 98.4 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 103.61 Å2 / Biso mean: 35.4643 Å2 / Biso min: 8.34 Å2
Refinement stepCycle: final / Resolution: 2.35→35.426 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14449 0 319 296 15064
Biso mean--28.32 27.76 -
Num. residues----1826
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00815207
X-RAY DIFFRACTIONf_angle_d1.03120686
X-RAY DIFFRACTIONf_chiral_restr0.0372238
X-RAY DIFFRACTIONf_plane_restr0.0052748
X-RAY DIFFRACTIONf_dihedral_angle_d14.1885639
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 (%)
2.35-2.37670.29153820.22670397421100
2.3767-2.40470.2413880.226770827470100
2.4047-2.4340.25023360.214469637299100
2.434-2.46480.27963940.223770767470100
2.4648-2.49720.27794090.21897060746999
2.4972-2.53140.26413200.225469977317100
2.5314-2.56760.27363380.21987073741199
2.5676-2.60590.2353960.20817090748699
2.6059-2.64660.25473450.21046996734199
2.6466-2.690.25654170.22216820723797
2.69-2.73630.24533970.21727054745199
2.7363-2.78610.23593540.21316972732699
2.7861-2.83960.25164000.21647019741999
2.8396-2.89760.26453610.21616929729099
2.8976-2.96050.27093620.21177005736799
2.9605-3.02940.2673540.21647073742799
3.0294-3.10510.27544120.21846863727599
3.1051-3.1890.28833710.22517019739098
3.189-3.28280.27673820.21726884726698
3.2828-3.38860.26783460.21717047739398
3.3886-3.50960.25763170.21846906722398
3.5096-3.650.23513550.20996930728598
3.65-3.8160.32643390.27296724706394
3.816-4.01690.2043590.17716799715897
4.0169-4.26820.19943540.17126865721997
4.2682-4.59710.17993740.15526905727998
4.5971-5.05850.18053860.15016852723897
5.0585-5.78770.21273440.18286968731298
5.7877-7.28150.20613550.18736977733299
7.2815-35.42960.16813840.15896782716696
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.2915-0.12810.26092.5268-0.49670.7168-0.03070.1437-0.0082-0.12390.06520.05020.037-0.00910.00370.1410.00640.00750.1583-0.02670.03244.97923.98013.1658
21.4740.31370.07162.5139-0.36440.7386-0.0548-0.0882-0.01410.12730.0610.1137-0.073-0.02270.00160.1783-0.0116-0.00150.20870.01950.15088.6603-23.267361.423
31.48720.2150.13452.61190.5570.8427-0.0009-0.16970.06410.11250.05-0.1290.00430.03780.00740.1466-0.0005-0.01960.1790.01560.08120.424925.027857.8739
41.5236-0.19040.13422.69430.34060.7488-0.04820.098-0.0549-0.11010.0572-0.1026-0.035-0.0266-0.00020.20690.01370.00120.1992-0.00210.151616.6754-24.09142.02
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A'A31 - 497
2X-RAY DIFFRACTION2chain 'B'B32 - 497
3X-RAY DIFFRACTION3chain 'C'C31 - 497
4X-RAY DIFFRACTION4chain 'D'D32 - 497

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