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- PDB-8vx0: CRYSTAL STRUCTURE OF CYP2C9*14 IN COMPLEX WITH LOSARTAN -

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Basic information

Entry
Database: PDB / ID: 8vx0
TitleCRYSTAL STRUCTURE OF CYP2C9*14 IN COMPLEX WITH LOSARTAN
ComponentsCytochrome P450 2C9
KeywordsOXIDOREDUCTASE / Cytochrome P450 2C9
Function / homology
Function and homology information


arachidonate 14,15-epoxygenase activity / arachidonate 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 ...arachidonate 14,15-epoxygenase activity / arachidonate 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 / icosanoid biosynthetic process / CYP2E1 reactions / arachidonate epoxygenase activity / epoxygenase P450 pathway / caffeine oxidase activity / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) / oxidative demethylation / Xenobiotics / steroid hydroxylase activity / 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 / xenobiotic catabolic process / cholesterol metabolic process / xenobiotic metabolic process / monooxygenase activity / 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
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: 3.05 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 2, 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

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Assembly

Deposited unit
A: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,3996
Polymers53,8021
Non-polymers1,5965
Water1,856103
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.209, 141.659, 161.879
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: 53802.328 Da / Num. of mol.: 1 / Mutation: R125H
Source method: isolated from a genetically manipulated source
Details: Cytochrome P450 2C9*14 genetic variant with amino acid substitution at position 125 from Arginine in CYP2C9 wild-type to Histidine in *14 as above.
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2C9, CYP2C10 / Variant: R125H / 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

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Non-polymers , 5 types, 108 molecules

#2: 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
#3: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#4: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / 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: 4.01 Å3/Da / Density % sol: 69.3 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.2 M Calcium acetate hydrate 0.1 M Tris, pH 7.5 15% w/v PEG4000
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: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 29, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.05→50.01 Å / Num. obs: 15658 / % possible obs: 97.68 % / Redundancy: 7.9 % / CC1/2: 0.98 / Rpim(I) all: 0.059 / Net I/σ(I): 11.3
Reflection shellResolution: 3.05→3.129 Å / Mean I/σ(I) obs: 7.5 / Num. unique obs: 1106 / CC1/2: 0.966 / Rpim(I) all: 0.075 / % possible all: 95.28

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
MOSFLMdata reduction
SCALAdata scaling
BALBESphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.05→50.01 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.911 / SU B: 12.111 / SU ML: 0.219 / Cross valid method: THROUGHOUT / ESU R Free: 0.327 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20586 852 5.2 %RANDOM
Rwork0.13867 ---
obs0.1422 15658 97.68 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.308 Å2
Baniso -1Baniso -2Baniso -3
1--1.76 Å20 Å20 Å2
2--0.52 Å20 Å2
3---1.24 Å2
Refinement stepCycle: 1 / Resolution: 3.05→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3691 0 109 103 3903
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0193914
X-RAY DIFFRACTIONr_bond_other_d0.0030.023781
X-RAY DIFFRACTIONr_angle_refined_deg2.1792.0065312
X-RAY DIFFRACTIONr_angle_other_deg2.21538745
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2165462
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.2824.32169
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.22715673
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.241518
X-RAY DIFFRACTIONr_chiral_restr0.2670.2592
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0214367
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02893
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_it3.6344.9591854
X-RAY DIFFRACTIONr_mcbond_other3.6274.9561853
X-RAY DIFFRACTIONr_mcangle_it5.7197.432314
X-RAY DIFFRACTIONr_mcangle_other5.7187.4342315
X-RAY DIFFRACTIONr_scbond_it4.215.3772060
X-RAY DIFFRACTIONr_scbond_other4.1545.372057
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.6727.8492993
X-RAY DIFFRACTIONr_long_range_B_refined10.18939.7694693
X-RAY DIFFRACTIONr_long_range_B_other9.99639.6634623
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.05→3.129 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.211 65 -
Rwork0.165 1106 -
obs--95.28 %

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