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- PDB-4nz2: Crystal structure of CYP2C9 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4nz2
TitleCrystal structure of CYP2C9 in complex with an inhibitor
ComponentsCytochrome P450 2C9CYP2C9
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / cytochrome P-450 / CYP2C9 / inhibitor / structure-based drug design / drug metabolism / monooxygenase / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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 / arachidonic acid epoxygenase activity / CYP2E1 reactions / epoxygenase P450 pathway / icosanoid biosynthetic process / 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 hydroxylase activity / 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-2QJ / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 2C9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.45 Å
AuthorsBranden, G. / Sjogren, T. / Xue, Y.
CitationJournal: Drug Discov Today / Year: 2014
Title: Structure-based ligand design to overcome CYP inhibition in drug discovery projects.
Authors: Branden, G. / Sjogren, T. / Schnecke, V. / Xue, Y.
History
DepositionDec 11, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 13, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cytochrome P450 2C9
B: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,92010
Polymers108,3372
Non-polymers2,5838
Water5,909328
1
A: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4605
Polymers54,1691
Non-polymers1,2914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 2C9
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4605
Polymers54,1691
Non-polymers1,2914
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)164.380, 164.380, 111.590
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number150
Space group name H-MP321

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Cytochrome P450 2C9 / CYP2C9 / (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 / Cytochrome P-450MP / Cytochrome P450 MP-4 / Cytochrome P450 MP-8 / Cytochrome P450 PB-1 / S-mephenytoin 4-hydroxylase


Mass: 54168.590 Da / Num. of mol.: 2 / Fragment: UNP residues 30-490 / Mutation: K206E, I215V, C216Y, S220P, P221A, I222L, I223
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2C10, CYP2C9, CYP2C9 CYP2C10 / Production host: Escherichia coli (E. coli) / Strain (production host): XL1 blue
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

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Non-polymers , 5 types, 336 molecules

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


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-2QJ / (2R)-N-{4-[(3-bromophenyl)sulfonyl]-2-chlorophenyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide


Mass: 486.688 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H12BrClF3NO4S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 328 / 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: 4.02 Å3/Da / Density % sol: 69.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8
Details: PEG 4000, LiSO4, Tris-HCl, DTT, glycerol, pH 8.0, VAPOR DIFFUSION, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0723 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 18, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.45→48.467 Å / Num. obs: 63852 / % possible obs: 99.8 % / Redundancy: 4 % / Biso Wilson estimate: 57.41 Å2 / Rmerge(I) obs: 0.067 / Net I/σ(I): 13.5
Reflection shellResolution: 2.45→2.51 Å / Redundancy: 4 % / Rmerge(I) obs: 0.526 / Mean I/σ(I) obs: 2.9 / Num. measured all: 18974 / Num. unique all: 4690 / % possible all: 99.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.2.21data scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
BUSTER2.10.0refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.45→48.467 Å / Cor.coef. Fo:Fc: 0.9302 / Cor.coef. Fo:Fc free: 0.9208 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.263 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2348 3238 5.07 %RANDOM
Rwork0.2167 ---
obs0.2176 63852 99.62 %-
Displacement parametersBiso max: 153.87 Å2 / Biso mean: 54.4935 Å2 / Biso min: 21.28 Å2
Baniso -1Baniso -2Baniso -3
1--3.795 Å20 Å20 Å2
2---3.795 Å20 Å2
3---7.5901 Å2
Refine analyzeLuzzati coordinate error obs: 0.389 Å
Refinement stepCycle: LAST / Resolution: 2.45→48.467 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7432 0 162 328 7922
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2688SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes184HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1132HARMONIC5
X-RAY DIFFRACTIONt_it7788HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion986SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9077SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7788HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg10574HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion2.06
X-RAY DIFFRACTIONt_other_torsion18.54
LS refinement shellResolution: 2.45→2.51 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3477 242 5.16 %
Rwork0.3241 4446 -
all0.3253 4688 -
obs-4688 99.62 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.774-0.4012-0.15160.7955-0.16171.3264-0.0632-0.03820.07310.02150.0464-0.0335-0.0494-0.02430.0168-0.11120.097-0.03110.0428-0.0328-0.0865-55.4525-48.919-20.8507
20.2553-0.11370.0251.31450.16591.7932-0.03930.02230.01230.03220.02010.02340.0329-0.07140.0192-0.13840.12310.00410.00550.0088-0.0356-20.8793-77.9792-30.4723
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A27 - 501
2X-RAY DIFFRACTION2{ B|* }B27 - 501

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