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- PDB-4k9u: Complex of human CYP3A4 with a desoxyritonavir analog -

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Basic information

Entry
Database: PDB / ID: 4k9u
TitleComplex of human CYP3A4 with a desoxyritonavir analog
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / cytochrome P450 3A4 / alpha-beta protein / cytochrome P450 fold / monooxygenase / cytochrome P450 reductase / endoplasmic reticulum / 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 / steroid hydroxylase activity / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / steroid binding / cholesterol metabolic process / xenobiotic metabolic process / monooxygenase activity / 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 ...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-5AW / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsSevrioukova, I.F. / Poulos, T.L.
CitationJournal: Biochemistry / Year: 2013
Title: Dissecting Cytochrome P450 3A4-Ligand Interactions Using Ritonavir Analogues.
Authors: Sevrioukova, I.F. / Poulos, T.L.
History
DepositionApr 21, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2013Group: Database references
Revision 1.2Jul 17, 2013Group: Database references
Revision 1.3Oct 29, 2014Group: Structure summary
Revision 1.4Oct 25, 2017Group: Author supporting evidence / Category: pdbx_struct_assembly_auth_evidence
Revision 1.5Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)57,4804
Polymers55,7581
Non-polymers1,7223
Water00
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)77.530, 99.880, 130.160
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
DetailsMONOMERIC ASSEMBLY CONFIRMED BY GEL FILTRATION (REFERENCE:SEVRIOUKOVA I.F. AND POULOS T.L., PNAS 2010, 107, 18422-18427)

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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: 55757.812 Da / Num. of mol.: 1 / Mutation: 3-22 deletion
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: human / Gene: CYP3A3, CYP3A4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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-5AW / N~2~-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-N-[(2S,5S)-5-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}hexan-2-yl]-D-valinamide


Mass: 552.753 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H40N6O4S2

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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: 2.26 Å3/Da / Density % sol: 45.56 %
Crystal growTemperature: 298 K / Method: microbatch under oil / pH: 5.5
Details: PEG 3350, sodium malonate, pH 5.5, microbatch under oil, temperature 298K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 8, 2012 / Details: mirrors
RadiationMonochromator: Yale mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→49.9 Å / Num. all: 12092 / Num. obs: 11886 / % possible obs: 98.3 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.3 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.9
Reflection shellResolution: 2.85→3 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.551 / Mean I/σ(I) obs: 2.2 / Num. unique all: 763 / % possible all: 99.7

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3NXU

3nxu


Resolution: 2.85→32.25 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.911 / SU B: 45.505 / SU ML: 0.395 / Cross valid method: THROUGHOUT / ESU R Free: 0.467 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.27851 572 4.8 %RANDOM
Rwork0.2134 ---
obs0.21666 11312 97.79 %-
all-11568 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 99.462 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å20 Å20 Å2
2--0.05 Å20 Å2
3----0.02 Å2
Refinement stepCycle: LAST / Resolution: 2.85→32.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3613 0 117 0 3730
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.023834
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.022.0255200
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.415447
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.17924.038156
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.52815677
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0981520
X-RAY DIFFRACTIONr_chiral_restr0.0980.2578
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212852
X-RAY DIFFRACTIONr_gen_planes_other
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_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.85→2.923 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.369 30 -
Rwork0.289 763 -
obs--99.5 %
Refinement TLS params.Method: refined / Origin x: 19.3878 Å / Origin y: 26.4031 Å / Origin z: 13.7016 Å
111213212223313233
T0.186 Å20.0349 Å20.0389 Å2-0.2631 Å20.0313 Å2--0.173 Å2
L2.0463 °21.7943 °2-0.416 °2-5.53 °2-1.2636 °2--2.3911 °2
S-0.1688 Å °0.0245 Å °-0.229 Å °-0.7128 Å °0.0246 Å °-0.1215 Å °0.4696 Å °0.1846 Å °0.1442 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A27 - 496
2X-RAY DIFFRACTION1A601 - 603

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