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- PDB-7rl2: Crystal Structure of the Human Cytochrome P450 2C9*8 (CYP2C9*8) G... -

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Basic information

Entry
Database: PDB / ID: 7rl2
TitleCrystal Structure of the Human Cytochrome P450 2C9*8 (CYP2C9*8) Genetic Variant in Complex with the Drug Losartan
ComponentsCytochrome P450 2C9
KeywordsOXIDOREDUCTASE / Cytochrome P450 / CYP2C9
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
PROTOPORPHYRIN IX CONTAINING FE / : / Chem-LSN / PHOSPHATE ION / Cytochrome P450 2C9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.23 Å
AuthorsShah, M.B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Int J Mol Sci / Year: 2021
Title: Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.
Authors: Parikh, S.J. / Kamat, S. / Phillips, M. / Boyson, S.P. / Yarbrough, T. / Davie, D. / Zhang, Q. / Glass, K.C. / Shah, M.B.
History
DepositionJul 23, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 27, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)55,8136
Polymers54,2171
Non-polymers1,5965
Water2,252125
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1600 Å2
ΔGint-29 kcal/mol
Surface area19680 Å2
Unit cell
Length a, b, c (Å)75.000, 143.211, 163.821
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-723-

HOH

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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: 54216.766 Da / Num. of mol.: 1 / Mutation: R150H, V490I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2C9, CYP2C10 / Variant: CYP2C9*8 / 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, 130 molecules

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


Mass: 616.487 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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
#4: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: K
#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.: 125 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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: 3.91 Å3/Da / Density % sol: 68.55 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 0.1 M HEPES pH 7.5, 30% w/v Polyethylene glycol 1000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.8856 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8856 Å / Relative weight: 1
ReflectionResolution: 2.23→40.27 Å / Num. obs: 42981 / % possible obs: 98.6 % / Redundancy: 7.4 % / Rmerge(I) obs: 0.128 / Net I/σ(I): 8.6
Reflection shellResolution: 2.23→2.35 Å / Redundancy: 7.4 % / Rmerge(I) obs: 1.734 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 42981 / % possible all: 99.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
SCALAdata scaling
PDB_EXTRACT3.27data extraction
iMOSFLMdata reduction
BALBESphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OG2

1og2


Resolution: 2.23→37.61 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.958 / SU B: 6.39 / SU ML: 0.147 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.166 / ESU R Free: 0.162 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.224 2135 5 %RANDOM
Rwork0.178 ---
obs0.18 40820 98.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 146.22 Å2 / Biso mean: 59.62 Å2 / Biso min: 33.09 Å2
Baniso -1Baniso -2Baniso -3
1--1.53 Å20 Å20 Å2
2--0.81 Å20 Å2
3---0.72 Å2
Refinement stepCycle: final / Resolution: 2.23→37.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3624 0 109 125 3858
Biso mean--54.98 62.07 -
Num. residues----463
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0133926
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173679
X-RAY DIFFRACTIONr_angle_refined_deg2.2061.6885332
X-RAY DIFFRACTIONr_angle_other_deg2.3291.6168584
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7415465
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.66223.027185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.49115674
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4931517
X-RAY DIFFRACTIONr_chiral_restr0.2770.2516
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.024329
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02808
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_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.23→2.283 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.44 141 -
Rwork0.423 3046 -
obs--99.5 %

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