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- PDB-4ny4: Crystal structure of CYP3A4 in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4ny4
TitleCrystal structure of CYP3A4 in complex with an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / cytochrome P-450 / CYP3A4 / inhibitor / structure-based drug design / drug metabolism / monooxygenase / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


quinine 3-monooxygenase / 1,8-cineole 2-exo-monooxygenase / albendazole monooxygenase (sulfoxide-forming) / quinine 3-monooxygenase activity / 1,8-cineole 2-exo-monooxygenase activity / 1-alpha,25-dihydroxyvitamin D3 23-hydroxylase activity / vitamin D3 25-hydroxylase activity / testosterone 6-beta-hydroxylase activity / vitamin D 24-hydroxylase activity / vitamin D catabolic process ...quinine 3-monooxygenase / 1,8-cineole 2-exo-monooxygenase / albendazole monooxygenase (sulfoxide-forming) / quinine 3-monooxygenase activity / 1,8-cineole 2-exo-monooxygenase activity / 1-alpha,25-dihydroxyvitamin D3 23-hydroxylase activity / vitamin D3 25-hydroxylase activity / testosterone 6-beta-hydroxylase activity / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / aflatoxin metabolic process / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / estrogen 2-hydroxylase activity / lipid hydroxylation / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / vitamin D metabolic process / Atorvastatin ADME / oxidative demethylation / : / steroid catabolic process / Xenobiotics / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinol metabolic process / retinoic acid metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / steroid hydroxylase activity / xenobiotic catabolic process / monooxygenase activity / steroid binding / cholesterol metabolic process / xenobiotic metabolic process / lipid metabolic process / oxygen binding / oxidoreductase activity / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / enzyme binding / cytoplasm
Similarity search - Function
Cytochrome P450, E-class, group II / Cytochrome P450, E-class, CYP3A / 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-2QH / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.95 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 10, 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 / 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 / _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

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,4323
Polymers55,3501
Non-polymers1,0822
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,72912
Polymers221,4014
Non-polymers4,3288
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
crystal symmetry operation3_455-x-1,y,-z1
crystal symmetry operation4_555x,-y,-z1
Buried area10030 Å2
ΔGint-149 kcal/mol
Surface area77780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.548, 101.692, 132.422
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222

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Components

#1: Protein Cytochrome P450 3A4 / 1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / Albendazole sulfoxidase / CYPIIIA3 ...1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / Albendazole sulfoxidase / CYPIIIA3 / CYPIIIA4 / Cytochrome P450 3A3 / Cytochrome P450 HLp / Cytochrome P450 NF-25 / Cytochrome P450-PCN1 / Nifedipine oxidase / Quinine 3-monooxygenase / Taurochenodeoxycholate 6-alpha-hydroxylase


Mass: 55350.289 Da / Num. of mol.: 1 / Fragment: UNP residues 24-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A3, CYP3A4, CYP3A4 CYP3A3 / Production host: Escherichia coli (E. coli) / Strain (production host): XL1 blue
References: UniProt: P08684, 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: P08684, 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: 1.14.13.157, EC: 1.14.13.32, EC: 1.14.13.67, EC: 1.14.13.97
#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-2QH / (8R)-3,3-difluoro-8-[4-fluoro-3-(pyridin-3-yl)phenyl]-8-(4-methoxy-3-methylphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine


Mass: 465.470 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H22F3N5O

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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: 2.39 Å3/Da / Density % sol: 48.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.2
Details: PEG 4000, CaCl2, glycerol, pH 7.2, 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: Mar 19, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.95→29.22 Å / Num. obs: 11344 / % possible obs: 98.8 % / Redundancy: 6.7 % / Biso Wilson estimate: 122.39 Å2 / Rmerge(I) obs: 0.061 / Net I/σ(I): 16.8
Reflection shellResolution: 2.95→3.11 Å / Redundancy: 7 % / Rmerge(I) obs: 0.633 / Mean I/σ(I) obs: 2.9 / Num. measured all: 11364 / Num. unique all: 1631 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.20data scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
BUSTER2.10.0refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.95→29.22 Å / Cor.coef. Fo:Fc: 0.9183 / Cor.coef. Fo:Fc free: 0.8945 / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2732 543 4.79 %RANDOM
Rwork0.249 ---
obs0.2502 11342 98.63 %-
Displacement parametersBiso max: 289.58 Å2 / Biso mean: 124.6155 Å2 / Biso min: 76.1 Å2
Baniso -1Baniso -2Baniso -3
1--3.0797 Å20 Å20 Å2
2--10.8661 Å20 Å2
3----7.7864 Å2
Refine analyzeLuzzati coordinate error obs: 0.91 Å
Refinement stepCycle: LAST / Resolution: 2.95→29.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3700 0 77 0 3777
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1331SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes84HARMONIC2
X-RAY DIFFRACTIONt_gen_planes555HARMONIC5
X-RAY DIFFRACTIONt_it3878HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion488SEMIHARMONIC5
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_contact4318SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3878HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg5265HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion1.65
X-RAY DIFFRACTIONt_other_torsion21.09
LS refinement shellResolution: 2.95→3.23 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.3308 135 5.01 %
Rwork0.274 2561 -
all0.2767 2696 -
obs-2696 98.63 %
Refinement TLS params.Method: refined / Origin x: -19.7098 Å / Origin y: -24.124 Å / Origin z: -14.1338 Å
111213212223313233
T-0.0049 Å20.0139 Å20.1515 Å2--0.008 Å2-0.0177 Å2--0.0019 Å2
L2.763 °2-1.4985 °2-1.9859 °2-3.0425 °20.7334 °2--1.9243 °2
S0.0063 Å °0.0606 Å °-0.0344 Å °0.0374 Å °-0.0417 Å °-0.0499 Å °-0.0182 Å °0.0503 Å °0.0353 Å °
Refinement TLS groupSelection details: { A|* }

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