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- PDB-3tda: Competitive replacement of thioridazine by prinomastat in crystal... -

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Basic information

Entry
Database: PDB / ID: 3tda
TitleCompetitive replacement of thioridazine by prinomastat in crystals of cytochrome P450 2D6
ComponentsCytochrome P450 2D6
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / monooxygenase / heme / prinomastat / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of binding / 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 ...negative regulation of binding / 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 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 / retinol metabolic process / estrogen 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 ...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 / Prinomastat / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.67 Å
AuthorsWang, A. / Stout, C.D. / Johnson, E.F.
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
DepositionAug 10, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 15, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 14, 2015Group: Database references
Revision 1.2Mar 11, 2015Group: Database references
Revision 1.3Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
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_conn.ptnr2_label_seq_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

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)219,40917
Polymers214,9224
Non-polymers4,48713
Water3,765209
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,9015
Polymers53,7311
Non-polymers1,1714
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8364
Polymers53,7311
Non-polymers1,1053
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8364
Polymers53,7311
Non-polymers1,1053
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8364
Polymers53,7311
Non-polymers1,1053
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.050, 192.740, 247.460
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#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
#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-PN0 / Prinomastat / (3S)-N-hydroxy-2,2-dimethyl-4-{[4-(pyridin-4-yloxy)phenyl]sulfonyl}thiomorpholine-3-carboxamide


Mass: 423.506 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H21N3O5S2 / Comment: inhibitor*YM
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 3.17 Å3/Da / Density % sol: 61.14 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEG3350, sodium acetate, sodium cacodylate, potassium phosphate, sodium chloride, zinc chloride, glycerol, beta-mercaptoethanol, prinomastat, thioridazine, HEGA-10, facial amphiphile 231_ ...Details: PEG3350, sodium acetate, sodium cacodylate, potassium phosphate, sodium chloride, zinc chloride, glycerol, beta-mercaptoethanol, prinomastat, thioridazine, HEGA-10, facial amphiphile 231_CHOL, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K, prinomastat was added after protein crystallization

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Apr 17, 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: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.668→42.186 Å / Num. all: 79050 / Num. obs: 79005 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Biso Wilson estimate: 54.275 Å2 / Rmerge(I) obs: 0.063 / Rsym value: 0.063 / Net I/σ(I): 6.3
Reflection shellResolution: 2.67→2.81 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.246 / Mean I/σ(I) obs: 2.8 / Num. unique all: 11348 / Rsym value: 0.246 / % 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: PDB ENTRY 3QM4

3qm4


Resolution: 2.67→42.04 Å / Rfactor Rfree error: 0.004 / Data cutoff high absF: 3017794.57 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.255 3916 5 %RANDOM
Rwork0.217 ---
obs0.217 78784 99.6 %-
all-78969 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 38.8196 Å2 / ksol: 0.37 e/Å3
Displacement parametersBiso mean: 44.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.44 Å20 Å2-0 Å2
2---12.65 Å2-0 Å2
3---13.1 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.39 Å0.32 Å
Luzzati d res low-5 Å
Luzzati sigma a0.43 Å0.31 Å
Refinement stepCycle: LAST / Resolution: 2.67→42.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14608 0 289 209 15106
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d21.5
X-RAY DIFFRACTIONc_improper_angle_d0.96
X-RAY DIFFRACTIONc_mcbond_it0.951
X-RAY DIFFRACTIONc_mcangle_it1.71.5
X-RAY DIFFRACTIONc_scbond_it1.371.5
X-RAY DIFFRACTIONc_scangle_it2.162
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.67→2.84 Å / Rfactor Rfree error: 0.013 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.329 664 5.1 %
Rwork0.278 12275 -
obs-11611 99.7 %
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 DIFFRACTION7pno.parpno.top

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