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- PDB-8vz7: Crystal Structure of Human Cytochrome P450 2C9*27 (R150L) Genetic... -

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Basic information

Entry
Database: PDB / ID: 8vz7
TitleCrystal Structure of Human Cytochrome P450 2C9*27 (R150L) Genetic Variant in Complex with the Drug Losartan
ComponentsCytochrome P450 2C9
KeywordsOXIDOREDUCTASE / Cytochrome P450 2C9*27 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, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
beta-D-fructofuranose / PROTOPORPHYRIN IX CONTAINING FE / : / Chem-LSN / Cytochrome P450 2C9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 Å
AuthorsShah, M.B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Inorg.Biochem. / Year: 2024
Title: Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan.
Authors: Parikh, S.J. / Edara, S. / Deodhar, S. / Singh, A.K. / Maekawa, K. / Zhang, Q. / Glass, K.C. / Shah, M.B.
History
DepositionFeb 11, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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)55,8736
Polymers54,1921
Non-polymers1,6825
Water3,081171
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.890, 142.170, 163.070
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 / Sugars , 2 types, 2 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: 54191.777 Da / Num. of mol.: 1 / Mutation: R150L, 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): Rosetta 2
References: UniProt: P11712, unspecific monooxygenase, (R)-limonene 6-monooxygenase, (S)-limonene 6-monooxygenase, (S)-limonene 7-monooxygenase
#4: Sugar ChemComp-FRU / beta-D-fructofuranose / beta-D-fructose / D-fructose / fructose


Type: D-saccharide, beta linking / Mass: 180.156 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H12O6
IdentifierTypeProgram
DFrufbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
b-D-fructofuranoseCOMMON NAMEGMML 1.0
b-D-FrufIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
FruSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 175 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.: 2 / Source method: obtained synthetically / Formula: C22H23ClN6O / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#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.: 171 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 4 Å3/Da / Density % sol: 69.29 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.3M Sodium Acetate Trihydrate 0.1 M Tris pH 7.5 25% w/v PEG 2000 MME
PH range: 7.4-7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: May 29, 2021
RadiationMonochromator: Liquid nitrogen-cooled double crystal Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.53→50.01 Å / Num. obs: 29365 / % possible obs: 99.8 % / Redundancy: 5.8 % / CC1/2: 0.996 / Rpim(I) all: 0.038 / Net I/σ(I): 12.8
Reflection shellResolution: 2.53→2.6 Å / Mean I/σ(I) obs: 5.2 / Num. unique obs: 2072 / CC1/2: 0.95 / Rpim(I) all: 0.121 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
SCALAdata scaling
iMOSFLMdata reduction
BALBESphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.53→50.01 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.941 / SU B: 6.848 / SU ML: 0.149 / Cross valid method: THROUGHOUT / ESU R: 0.242 / ESU R Free: 0.216 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21531 1494 5.1 %RANDOM
Rwork0.15092 ---
obs0.15423 27822 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 60.981 Å2
Baniso -1Baniso -2Baniso -3
1--1.97 Å20 Å20 Å2
2--0.02 Å20 Å2
3---1.95 Å2
Refinement stepCycle: 1 / Resolution: 2.53→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3676 0 116 171 3963
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0193934
X-RAY DIFFRACTIONr_bond_other_d0.0020.023809
X-RAY DIFFRACTIONr_angle_refined_deg2.0522.0135337
X-RAY DIFFRACTIONr_angle_other_deg1.4938815
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6585462
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.95324.345168
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.91215680
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0491518
X-RAY DIFFRACTIONr_chiral_restr0.1560.2598
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214299
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02883
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_it4.9165.6421854
X-RAY DIFFRACTIONr_mcbond_other4.9135.6381853
X-RAY DIFFRACTIONr_mcangle_it6.9128.4412314
X-RAY DIFFRACTIONr_mcangle_other6.9118.4472315
X-RAY DIFFRACTIONr_scbond_it6.6396.2862080
X-RAY DIFFRACTIONr_scbond_other6.5546.2772076
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other9.5479.123018
X-RAY DIFFRACTIONr_long_range_B_refined16.45748.0014968
X-RAY DIFFRACTIONr_long_range_B_other16.03546.9864750
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.534→2.6 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 100 -
Rwork0.216 2072 -
obs--99.91 %

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