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- PDB-3t3r: Human Cytochrome P450 2A6 in complex with Pilocarpine -

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Basic information

Entry
Database: PDB / ID: 3t3r
TitleHuman Cytochrome P450 2A6 in complex with Pilocarpine
ComponentsCytochrome P450 2A6
KeywordsOXIDOREDUCTASE / CYP2A6 / cytochrome P450 2A6 / P450 2A6 / heme protein / monooxygenase / drug metabolism / xenobiotic metabolism / endoplasmic reticulum / membrane
Function / homology
Function and homology information


coumarin catabolic process / coumarin 7-hydroxylase activity / 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 epoxygenase activity / epoxygenase P450 pathway / 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 / cytoplasmic microtubule ...coumarin catabolic process / coumarin 7-hydroxylase activity / 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 epoxygenase activity / epoxygenase P450 pathway / 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 / cytoplasmic microtubule / steroid metabolic process / xenobiotic catabolic process / xenobiotic metabolic process / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / enzyme binding / cytoplasm
Similarity search - Function
Cytochrome P450, E-class, group I, CYP2A-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, CYP2A-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
Chem-9PL / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 2A6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsDeVore, N.M. / Scott, E.E.
CitationJournal: Febs J. / Year: 2012
Title: Structural comparison of cytochromes P450 2A6, 2A13, and 2E1 with pilocarpine.
Authors: DeVore, N.M. / Meneely, K.M. / Bart, A.G. / Stephens, E.S. / Battaile, K.P. / Scott, E.E.
History
DepositionJul 25, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2011Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2012Group: Database references
Revision 1.2Nov 8, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.name
Revision 1.3Sep 13, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / 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_label_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_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

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 2A6
B: Cytochrome P450 2A6
C: Cytochrome P450 2A6
D: Cytochrome P450 2A6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,98612
Polymers218,6874
Non-polymers3,2998
Water3,909217
1
A: Cytochrome P450 2A6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4963
Polymers54,6721
Non-polymers8252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 2A6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4963
Polymers54,6721
Non-polymers8252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Cytochrome P450 2A6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4963
Polymers54,6721
Non-polymers8252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Cytochrome P450 2A6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4963
Polymers54,6721
Non-polymers8252
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.336, 158.005, 104.453
Angle α, β, γ (deg.)90.00, 92.10, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Cytochrome P450 2A6 / CYPIIA6 / Coumarin 7-hydroxylase / Cytochrome P450 IIA3 / Cytochrome P450(I)


Mass: 54671.637 Da / Num. of mol.: 4 / Fragment: unp residues 29-494 / Mutation: Y392F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2A3, CYP2A6 / Plasmid: pKK2A6dH / Production host: Escherichia coli (E. coli) / Strain (production host): TOPP3 / References: UniProt: P11509, 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-9PL / (3S,4R)-3-ethyl-4-[(1-methyl-1H-imidazol-5-yl)methyl]dihydrofuran-2(3H)-one / PILOCARPINE


Mass: 208.257 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H16N2O2 / Comment: medication, alkaloid*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 217 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsAUTHORS STATE THAT THE AMINOACID AT POSITION 392 OF THE UNIPROT ENTRY P11509 SHOULD BE A TYR

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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: 2.65 Å3/Da / Density % sol: 53.62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 30% PEG 3350, 0.175 M Tris, pH 8.5, 0.20 M ammomium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jun 28, 2008 / Details: Rh coated flat mirror, toroidal focusing mirror
RadiationMonochromator: Double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.4→87.04 Å / Num. all: 237442 / Num. obs: 85624 / % possible obs: 96.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Biso Wilson estimate: 41.4 Å2 / Rmerge(I) obs: 0.075 / Rsym value: 0.106 / Net I/σ(I): 13.2
Reflection shellResolution: 2.4→2.46 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.402 / Mean I/σ(I) obs: 3.4 / Num. unique all: 17456 / % possible all: 97.9

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERMRphasing
REFMAC5.5.0072refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: CYP2A6 PDB entry 1Z10

1z10


Resolution: 2.4→79 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.893 / SU B: 8.008 / SU ML: 0.191 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.281
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
RfactorNum. reflection% reflectionSelection details
Rfree0.26029 4277 5 %RANDOM
Rwork0.19898 ---
all0.20215 81313 --
obs0.20215 81313 96.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 30.545 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0 Å2-0 Å2
2---0.01 Å2-0 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.277 Å
Refinement stepCycle: LAST / Resolution: 2.4→79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14998 0 232 217 15447
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.02215689
X-RAY DIFFRACTIONr_angle_refined_deg1.8472.00121205
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.15251865
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.96423.286773
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.049152748
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.70315131
X-RAY DIFFRACTIONr_chiral_restr0.1340.22209
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02112093
X-RAY DIFFRACTIONr_mcbond_it0.8711.59257
X-RAY DIFFRACTIONr_mcangle_it1.608215012
X-RAY DIFFRACTIONr_scbond_it2.63636432
X-RAY DIFFRACTIONr_scangle_it4.0884.56185
LS refinement shellResolution: 2.4→2.462 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.291 317 -
Rwork0.218 6095 -
obs--97.8 %

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