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- PDB-5w0c: Cytochrome P450 (CYP) 2C9 TCA007 Inhibitor Complex -

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Basic information

Entry
Database: PDB / ID: 5w0c
TitleCytochrome P450 (CYP) 2C9 TCA007 Inhibitor Complex
ComponentsCytochrome P450 2C9
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / Inhibitor Complex / P450 Monooxygenase / Cytochrome P450 2C9 / CYP2C9 / OXIDOREDUCTASE-OXIDOREDUCTASE inhibitor complex
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 / CYP2E1 reactions / arachidonate epoxygenase activity / icosanoid biosynthetic process / 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 / xenobiotic metabolic process / cholesterol 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 / 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
Chem-9W6 / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 2C9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.001 Å
AuthorsJohnson, E.F. / Hsu, M.-H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM031001 United States
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2017
Title: Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes.
Authors: Liu, R. / Lyu, X. / Batt, S.M. / Hsu, M.H. / Harbut, M.B. / Vilcheze, C. / Cheng, B. / Ajayi, K. / Yang, B. / Yang, Y. / Guo, H. / Lin, C. / Gan, F. / Wang, C. / Franzblau, S.G. / Jacobs, W. ...Authors: Liu, R. / Lyu, X. / Batt, S.M. / Hsu, M.H. / Harbut, M.B. / Vilcheze, C. / Cheng, B. / Ajayi, K. / Yang, B. / Yang, Y. / Guo, H. / Lin, C. / Gan, F. / Wang, C. / Franzblau, S.G. / Jacobs, W.R. / Besra, G.S. / Johnson, E.F. / Petrassi, M. / Chatterjee, A.K. / Futterer, K. / Wang, F.
History
DepositionMay 30, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 13, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2017Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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)55,4084
Polymers54,3231
Non-polymers1,0853
Water3,801211
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.394, 91.394, 169.225
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#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: 54322.887 Da / Num. of mol.: 1 / Fragment: UNP residues 23-489
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2C9, CYP2C10 / Plasmid: pCWORI / Production host: Escherichia coli DH5[alpha] (bacteria) / Strain (production host): DH5[alpha]
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
#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-9W6 / ethyl {2-[([1,3]thiazolo[4,5-c]pyridine-2-carbonyl)amino]thiophene-3-carbonyl}carbamate


Mass: 376.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H12N4O4S2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / Source method: isolated from a natural source / Formula: H2O

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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: 2.5 Å3/Da / Density % sol: 50.88 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: PEG 3350, HEPES, CYMAL-5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 17, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2→38.54 Å / Num. obs: 35507 / % possible obs: 99.7 % / Redundancy: 5.8 % / Biso Wilson estimate: 31.3 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.021 / Net I/av σ(I): 21.6 / Net I/σ(I): 11.8
Reflection shellResolution: 2→2.05 Å / Redundancy: 5.7 % / Rmerge(I) obs: 0.436 / Mean I/σ(I) obs: 4.1 / Num. unique obs: 2598 / CC1/2: 0.884 / Rpim(I) all: 0.2 / % possible all: 97.9

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1R9O

1r9o


Resolution: 2.001→38.535 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.61 / Phase error: 22.11
RfactorNum. reflection% reflection
Rfree0.2258 1717 4.84 %
Rwork0.1815 --
obs0.1836 35497 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.001→38.535 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3710 0 74 213 3997
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083884
X-RAY DIFFRACTIONf_angle_d0.8815263
X-RAY DIFFRACTIONf_dihedral_angle_d11.9812350
X-RAY DIFFRACTIONf_chiral_restr0.052571
X-RAY DIFFRACTIONf_plane_restr0.006695
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0008-2.05970.27381600.21532781X-RAY DIFFRACTION98
2.0597-2.12620.24741320.2022833X-RAY DIFFRACTION100
2.1262-2.20210.24291450.19552812X-RAY DIFFRACTION100
2.2021-2.29030.23891350.19332816X-RAY DIFFRACTION100
2.2903-2.39450.2281360.18932843X-RAY DIFFRACTION100
2.3945-2.52070.23841640.18922792X-RAY DIFFRACTION100
2.5207-2.67860.2621150.20052838X-RAY DIFFRACTION100
2.6786-2.88540.23841440.19942799X-RAY DIFFRACTION99
2.8854-3.17560.22891560.22791X-RAY DIFFRACTION100
3.1756-3.63490.25961230.18572856X-RAY DIFFRACTION100
3.6349-4.57840.21191660.15772810X-RAY DIFFRACTION100
4.5784-38.54220.18751410.16352809X-RAY DIFFRACTION100

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