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- PDB-6vlt: Crystal Structure of Human P450 2C9*2 Genetic Variant in Complex ... -

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Basic information

Entry
Database: PDB / ID: 6vlt
TitleCrystal Structure of Human P450 2C9*2 Genetic Variant in Complex with Losartan
ComponentsCytochrome P450 2C9
KeywordsOXIDOREDUCTASE / CYP2C9*2 / CYP2C9 R144C
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 / urea 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 / urea metabolic process / omega-hydroxylase P450 pathway / Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) / organic acid metabolic process / organofluorine metabolic process / CYP2E1 reactions / arachidonate epoxygenase activity / icosanoid biosynthetic process / epoxygenase P450 pathway / monocarboxylic acid metabolic process / caffeine oxidase activity / Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / steroid hydroxylase activity / 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 / estrogen metabolic process / unspecific monooxygenase / long-chain fatty acid biosynthetic process / 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 / Cytochrome P450 2C9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.12 Å
AuthorsShah, M.B.
Funding support United States, 1items
OrganizationGrant numberCountry
American Heart Association19AIREA34450040 United States
CitationJournal: Mol.Pharmacol. / Year: 2020
Title: Structure of Cytochrome P450 2C9*2 in Complex with Losartan: Insights into the Effect of Genetic Polymorphism.
Authors: Parikh, S.J. / Evans, C.M. / Obi, J.O. / Zhang, Q. / Maekawa, K. / Glass, K.C. / Shah, M.B.
History
DepositionJan 25, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Apr 3, 2024Group: Refinement description / Category: 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
B: Cytochrome P450 2C9
C: Cytochrome P450 2C9
D: Cytochrome P450 2C9
E: Cytochrome P450 2C9
F: Cytochrome P450 2C9
G: Cytochrome P450 2C9
H: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)446,01435
Polymers433,4548
Non-polymers12,56027
Water2,576143
1
A: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,2213
Polymers54,1821
Non-polymers1,0392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,2213
Polymers54,1821
Non-polymers1,0392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,2213
Polymers54,1821
Non-polymers1,0392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,2213
Polymers54,1821
Non-polymers1,0392
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,3066
Polymers54,1821
Non-polymers2,1255
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,3066
Polymers54,1821
Non-polymers2,1255
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
7
G: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,3066
Polymers54,1821
Non-polymers2,1255
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
8
H: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,2105
Polymers54,1821
Non-polymers2,0294
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)238.100, 238.100, 109.851
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number144
Space group name H-MP31

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Components

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Protein , 1 types, 8 molecules ABCDEFGH

#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: 54181.762 Da / Num. of mol.: 8 / Mutation: R144C, 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, unspecific monooxygenase, (R)-limonene 6-monooxygenase, (S)-limonene 6-monooxygenase, (S)-limonene 7-monooxygenase

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Non-polymers , 5 types, 170 molecules

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


Mass: 616.487 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#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.: 8 / Source method: obtained synthetically / Formula: C22H23ClN6O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CM5 / 5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE / 5-CYCLOHEXYLPENTYL 4-O-ALPHA-D-GLUCOPYRANOSYL-BETA-D-GLUCOPYRANOSIDE / CYMAL-5


Mass: 494.573 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C23H42O11 / Comment: detergent*YM
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 143 / 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: 4.26 Å3/Da / Density % sol: 71.1 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1M Lithium sulfate monohydrate, 0.1M Sodium citrate tribasic dehydrate pH 5.5, 20% 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: 0.9 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 3.12→50.01 Å / Num. obs: 122890 / % possible obs: 99.3 % / Redundancy: 8.1 % / Rpim(I) all: 0.127 / Rrim(I) all: 0.367 / Net I/σ(I): 8.1
Reflection shellResolution: 3.12→3.29 Å / Redundancy: 8.2 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 17998 / Rpim(I) all: 1.2 / % possible all: 99.8

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Processing

Software
NameVersionClassification
SCALAdata scaling
REFMAC5.8.0103refinement
PDB_EXTRACT3.25data extraction
iMOSFLMdata processing
BALBESphasing
Cootmodel building
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1OG

Resolution: 3.12→50.01 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.922 / SU B: 17.179 / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.361
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2211 6047 4.9 %RANDOM
Rwork0.1556 ---
obs0.1588 116701 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 201.6 Å2 / Biso mean: 79.914 Å2 / Biso min: 20 Å2
Baniso -1Baniso -2Baniso -3
1-0.83 Å20.42 Å20 Å2
2--0.83 Å20 Å2
3----2.71 Å2
Refinement stepCycle: final / Resolution: 3.12→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms28768 0 871 143 29782
Biso mean--87.93 60.52 -
Num. residues----3684
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.01930886
X-RAY DIFFRACTIONr_bond_other_d0.0040.0229554
X-RAY DIFFRACTIONr_angle_refined_deg1.8562.00841969
X-RAY DIFFRACTIONr_angle_other_deg1.2223.00368291
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.64353663
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.15624.3671319
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.147155206
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.65515138
X-RAY DIFFRACTIONr_chiral_restr0.1050.24684
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02134014
X-RAY DIFFRACTIONr_gen_planes_other0.0040.026916
LS refinement shellResolution: 3.122→3.203 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.333 417 -
Rwork0.274 8634 -
all-9051 -
obs--99.45 %

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