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- PDB-3qm4: Human Cytochrome P450 (CYP) 2D6 - Prinomastat Complex -

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Basic information

Entry
Database: PDB / ID: 3qm4
TitleHuman Cytochrome P450 (CYP) 2D6 - Prinomastat Complex
ComponentsCytochrome P450 2D6CYP2D6
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / CYP2D6 / P450 2D6 / P450 / MONOOXYGENASE / Prinomastat / HEME / 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 / xenobiotic metabolic process / cholesterol 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 / NICKEL (II) ION / Prinomastat / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsWang, A. / Stout, C.D. / Johnson, E.F.
CitationJournal: J.Biol.Chem. / Year: 2012
Title: Crystal Structure of Human Cytochrome P450 2D6 with Prinomastat Bound.
Authors: Wang, A. / Savas, U. / Hsu, M.H. / Stout, C.D. / Johnson, E.F.
History
DepositionFeb 3, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2012Group: Database references
Revision 1.2Jul 4, 2012Group: Database references
Revision 1.3Jul 18, 2012Group: Database references
Revision 1.4Sep 13, 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 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
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.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.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_ref_seq_dif.details / _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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)109,6007
Polymers107,4612
Non-polymers2,1395
Water1267
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4750 Å2
ΔGint-54 kcal/mol
Surface area37000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)194.540, 55.070, 145.870
Angle α, β, γ (deg.)90.00, 134.97, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 53730.566 Da / Num. of mol.: 2 / Fragment: RESIDUES 34-497
Source method: isolated from a genetically manipulated source
Details: N-terminal modification by replacing WT human P450 2D6 1MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARY33 with 23MAKKTSSKGKL33; C-terminal modification: His tag extension with 498HHHH501
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 / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-PN0 / Prinomastat / (3S)-N-hydroxy-2,2-dimethyl-4-{[4-(pyridin-4-yloxy)phenyl]sulfonyl}thiomorpholine-3-carboxamide / Prinomastat


Mass: 423.506 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H21N3O5S2 / Comment: inhibitor*YM
#4: Chemical ChemComp-NI / NICKEL (II) ION / Nickel


Mass: 58.693 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ni
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 7 / 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: 2.57 Å3/Da / Density % sol: 52.18 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEG-3350, ammonium sulphate, sodium cacodylate, potassium phosphate, NaCl, glycerol, beta-mercaptoethanol, prinomastat, HEGA-10, CHAPS, pH 7, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.97945 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 18, 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: 0.97945 Å / Relative weight: 1
ReflectionResolution: 2.85→40.82 Å / Num. all: 25762 / Num. obs: 25762 / % possible obs: 99.3 % / Observed criterion σ(F): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 77.9 Å2 / Rmerge(I) obs: 0.065 / Rsym value: 0.065 / Net I/σ(I): 8.6
Reflection shellResolution: 2.85→3 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.468 / Mean I/σ(I) obs: 1.6 / Num. unique all: 3755 / Rsym value: 0.468 / % possible all: 99.9

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
CNS1.3refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2f9q

2f9q


Resolution: 2.85→41 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1384624.8 / Data cutoff low absF: 0 / Isotropic thermal model: Isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.288 1314 5.1 %RANDOM
Rwork0.243 ---
all0.245 25992 --
obs0.245 25690 98.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 38.1079 Å2 / ksol: 0.32 e/Å3
Displacement parametersBiso mean: 77.5 Å2
Baniso -1Baniso -2Baniso -3
1--25.37 Å20 Å212.02 Å2
2--35.44 Å20 Å2
3----10.07 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.54 Å0.43 Å
Luzzati d res low-5 Å
Luzzati sigma a0.77 Å0.7 Å
Refinement stepCycle: LAST / Resolution: 2.85→41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7295 0 143 7 7445
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.1
X-RAY DIFFRACTIONc_improper_angle_d1.07
X-RAY DIFFRACTIONc_mcbond_it1.21.5
X-RAY DIFFRACTIONc_mcangle_it2.112
X-RAY DIFFRACTIONc_scbond_it1.622
X-RAY DIFFRACTIONc_scangle_it2.612.5
Refine LS restraints NCSNCS model details: CONSTR
LS refinement shellResolution: 2.85→3.03 Å / Rfactor Rfree error: 0.029 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.418 210 4.9 %
Rwork0.388 4052 -
obs-4052 99.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2dna-rna_rep.paramdna-rna.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5carbohydrate.paramcarbohydrate.top
X-RAY DIFFRACTION6xdict_heme.parxdict_heme.top
X-RAY DIFFRACTION7lig.parlig.top

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