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- PDB-4d7d: Cytochrome P450 3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d7d
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 / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-PKT / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.76 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 22, 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)56,8433
Polymers55,7581
Non-polymers1,0852
Water18010
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.138, 101.332, 127.966
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 / TAUROCHENODEOXYCHOLA TE 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-PKT / tert-butyl [(2S)-1-(1H-indol-3-yl)-3-({3-oxo-3-[(pyridin-3-ylmethyl)amino]propyl}sulfanyl)propan-2-yl]carbamate


Mass: 468.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32N4O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsNEEDS TO BE NAMED (PKT): FIGURE WITH THE PKT STRUCTURE IS ATTACHED

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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: 2.53 Å3/Da / Density % sol: 51.47 % / Description: NONE
Crystal growMethod: microbatch / pH: 5
Details: MICROBATCH UNDER OIL WITH 11% PEG 3350 AND 60 MM SODIUM MALONATE PH 5.0

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.98
DetectorType: ADSC CCD / Detector: CCD / Date: Jul 27, 2013 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.76→37.4 Å / Num. obs: 13205 / % possible obs: 98.3 % / Observed criterion σ(I): 2 / Redundancy: 9.6 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 13.7
Reflection shellResolution: 2.76→2.91 Å / Redundancy: 8 % / Rmerge(I) obs: 1.5 / Mean I/σ(I) obs: 1.1 / % possible all: 89

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Processing

Software
NameVersionClassification
REFMAC5.6refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1TQN

1tqn


Resolution: 2.76→37.44 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.925 / SU B: 41.794 / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0 / ESU R Free: 0.435 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 265-266 AND 281-288 ARE DISORDERED
RfactorNum. reflection% reflectionSelection details
Rfree0.27778 645 4.9 %RANDOM
Rwork0.2003 ---
obs0.20401 12401 97.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 109.133 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20 Å2
2---0.05 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.76→37.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3689 0 76 10 3775
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.023863
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9342.0135240
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4515455
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.70623.851161
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.04515689
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2411522
X-RAY DIFFRACTIONr_chiral_restr0.0970.2575
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212879
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_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
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: 2.762→2.833 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.356 36 -
Rwork0.325 656 -
obs--74.49 %
Refinement TLS params.Method: refined / Origin x: -19.543 Å / Origin y: 23.9665 Å / Origin z: 13.0517 Å
111213212223313233
T0.1015 Å20.0227 Å2-0.0039 Å2-0.198 Å2-0.0427 Å2--0.1049 Å2
L2.1436 °21.3521 °20.607 °2-4.6299 °20.9822 °2--2.395 °2
S-0.1209 Å °-0.1248 Å °0.2489 Å °-0.5207 Å °0.0174 Å °0.0311 Å °-0.3763 Å °-0.1712 Å °0.1034 Å °

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