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- PDB-4d78: Cytochrome P450 3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d78
TitleCytochrome P450 3A4 bound to an inhibitor
ComponentsCYTOCHROME P450 3A4
KeywordsOXIDOREDUCTASE / MONOOXYGENASE / HUMAN CYP3A4 / INHIBITORY 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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity ...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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / lipid hydroxylation / aflatoxin metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / testosterone 6-beta-hydroxylase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / vitamin D metabolic process / steroid catabolic process / Atorvastatin ADME / steroid hydroxylase activity / Xenobiotics / Phase I - Functionalization of compounds / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / unspecific monooxygenase / long-chain fatty acid biosynthetic process / Prednisone ADME / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / cholesterol metabolic process / steroid binding / xenobiotic metabolic process / monooxygenase activity / oxygen binding / lipid metabolic process / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-J9K / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSevrioukova, I. / Poulos, T.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Structure-Based Inhibitor Design for Evaluation of a Cyp3A4 Pharmacophore Model.
Authors: Kaur, P. / Chamberlin, R. / Poulos, T.L. / Sevrioukova, I.F.
History
DepositionNov 21, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 23, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2015Group: Database references
Revision 1.2May 25, 2016Group: Database references
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_biol
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9885
Polymers55,7581
Non-polymers1,2304
Water1086
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.920, 100.360, 124.750
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 55757.812 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 23-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PCWORI / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
References: UniProt: P08684, 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-J9K / tert-butyl [(2S)-1-({3-oxo-3-[(pyridin-3-ylmethyl)amino]propyl}sulfanyl)-3-phenylpropan-2-yl]carbamate


Mass: 429.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H31N3O3S
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsNEEDS TO BE NAMED (LIG): FIGURE WITH THE HETEROGROUP STRUCTURE WILL BE EMAILED SEPARATELY

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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: 2.38 Å3/Da / Density % sol: 48.3 % / Description: NONE
Crystal growMethod: microbatch / pH: 5
Details: MICROBATCH UNDER OIL WITH 10% PEG 3350 AND 80 MM SODIUM MALONATE PH 5.0

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 24, 2013 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→65.9 Å / Num. obs: 12092 / % possible obs: 100 % / Observed criterion σ(I): 2 / Redundancy: 5.6 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 10.6
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 1.9 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1TQN

1tqn


Resolution: 2.8→64.85 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.9 / SU B: 41.476 / SU ML: 0.37 / Cross valid method: THROUGHOUT / ESU R Free: 0.446 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 265-266 AND 280-288 ARE DISORDERED
RfactorNum. reflection% reflectionSelection details
Rfree0.27237 576 4.8 %RANDOM
Rwork0.19295 ---
obs0.19702 11496 99.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 102.012 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å2-0 Å20 Å2
2---0.56 Å20 Å2
3---0.33 Å2
Refinement stepCycle: LAST / Resolution: 2.8→64.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3698 0 85 6 3789
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0193887
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4832.0125268
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1955457
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.73323.827162
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.85715691
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1331522
X-RAY DIFFRACTIONr_chiral_restr0.1040.2581
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212887
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_it3.7526.6871837
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.96610.0252291
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.2866.892049
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.433 43 -
Rwork0.33 832 -
obs--99.43 %
Refinement TLS params.Method: refined / Origin x: -19.0755 Å / Origin y: 26.4684 Å / Origin z: -12.4506 Å
111213212223313233
T0.1821 Å2-0.0365 Å20.0201 Å2-0.0803 Å2-0.053 Å2--0.0747 Å2
L2.6907 °2-1.1724 °2-0.5123 °2-4.7655 °20.8918 °2--2.5135 °2
S-0.163 Å °0.124 Å °-0.3499 Å °0.5974 Å °0.073 Å °0.1712 Å °0.4937 Å °-0.1968 Å °0.09 Å °

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