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- PDB-5x23: Crystal structure of CYP2C9 genetic variant A477T (*30) in comple... -

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Basic information

Entry
Database: PDB / ID: 5x23
TitleCrystal structure of CYP2C9 genetic variant A477T (*30) in complex with multiple losartan molecules
ComponentsCytochrome P450 2C9
KeywordsOXIDOREDUCTASE / CYP2C9 polymorphic mutant / Single Nucleotide Polymorphism / P450 2C9 genetic variant
Function / homology
Function and homology information


arachidonic acid 14,15-epoxygenase activity / arachidonic acid 11,12-epoxygenase activity / amide metabolic process / (S)-limonene 6-monooxygenase / (S)-limonene 7-monooxygenase / (R)-limonene 6-monooxygenase / (S)-limonene 6-monooxygenase activity / (S)-limonene 7-monooxygenase activity / (R)-limonene 6-monooxygenase activity / monocarboxylic acid metabolic process ...arachidonic acid 14,15-epoxygenase activity / arachidonic acid 11,12-epoxygenase activity / amide metabolic process / (S)-limonene 6-monooxygenase / (S)-limonene 7-monooxygenase / (R)-limonene 6-monooxygenase / (S)-limonene 6-monooxygenase activity / (S)-limonene 7-monooxygenase activity / (R)-limonene 6-monooxygenase activity / monocarboxylic acid metabolic process / urea metabolic process / Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) / omega-hydroxylase P450 pathway / CYP2E1 reactions / arachidonic acid epoxygenase activity / icosanoid biosynthetic process / epoxygenase P450 pathway / caffeine oxidase activity / Biosynthesis of maresin-like SPMs / Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) / 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 / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / steroid hydroxylase activity / xenobiotic catabolic process / monooxygenase activity / cholesterol metabolic process / xenobiotic metabolic process / oxidoreductase activity / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / plasma membrane / cytoplasm
Similarity search - Function
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 / : / Chem-LSN / PHOSPHATE ION / Cytochrome P450 2C9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsMaekawa, K. / Adachi, M. / Shah, M.B.
Funding support Japan, 2items
OrganizationGrant numberCountry
KAKENHI22590054 Japan
KAKENHI25293128 Japan
CitationJournal: Biochemistry / Year: 2017
Title: Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9
Authors: Maekawa, K. / Adachi, M. / Matsuzawa, Y. / Zhang, Q. / Kuroki, R. / Saito, Y. / Shah, M.B.
History
DepositionJan 30, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,2857
Polymers54,2661
Non-polymers2,0196
Water3,549197
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1590 Å2
ΔGint-28 kcal/mol
Surface area19590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.952, 142.273, 161.831
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Cytochrome P450 2C9 / (R)-limonene 6-monooxygenase / (S)-limonene 6-monooxygenase / (S)-limonene 7-monooxygenase / ...(R)-limonene 6-monooxygenase / (S)-limonene 6-monooxygenase / (S)-limonene 7-monooxygenase / CYPIIC9 / Cholesterol 25-hydroxylase / Cytochrome P-450MP / Cytochrome P450 MP-4 / Cytochrome P450 MP-8 / Cytochrome P450 PB-1 / S-mephenytoin 4-hydroxylase


Mass: 54265.836 Da / Num. of mol.: 1 / Fragment: UNP residues 24-490 / Mutation: A477T, V490I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2C9, CYP2C10 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2
References: UniProt: P11712, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With NADH or NADPH as one donor, and incorporation of one atom of oxygen ...References: UniProt: P11712, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With NADH or NADPH as one donor, and incorporation of one atom of oxygen into the other donor, EC: 1.14.13.80, EC: 1.14.13.48, EC: 1.14.13.49, EC: 1.14.99.38

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Non-polymers , 5 types, 203 molecules

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


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-LSN / [2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol / Losartan


Mass: 422.911 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C22H23ClN6O / Comment: medication*YM
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsThe N-terminal transmembrane anchor domain (residues 1-23 in P11712) was replaced with MAKKT.

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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: 3.84 Å3/Da / Density % sol: 67.93 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 1.5 M ammonium sulfate, 0.1 M Tris pH8.5, 12% glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jun 13, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2→45.51 Å / Num. obs: 58476 / % possible obs: 99.1 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 32.2
Reflection shellResolution: 2→2.07 Å / Rmerge(I) obs: 0.59 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 5733 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.5.0072refinement
HKL-2000data reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R9O

1r9o


Resolution: 2→45.51 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.944 / SU B: 4.858 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.145 / ESU R Free: 0.141 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25308 2964 5.1 %RANDOM
Rwork0.21738 ---
obs0.21923 55512 99.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso mean: 49.992 Å2
Baniso -1Baniso -2Baniso -3
1--0.68 Å20 Å20 Å2
2--0.78 Å20 Å2
3----0.1 Å2
Refinement stepCycle: 1 / Resolution: 2→45.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3660 0 139 197 3996
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0223898
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.5012.0265297
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.8445462
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.43524.32169
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.8215664
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.9291519
X-RAY DIFFRACTIONr_chiral_restr0.3330.2591
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.0213051
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3751.52322
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.50323784
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.54131576
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.6424.51513
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.997→2.049 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.494 237 -
Rwork0.478 3984 -
obs--98.14 %

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