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- PDB-4d6z: Cytochrome P450 3A4 bound to imidazole and an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d6z
TitleCytochrome P450 3A4 bound to imidazole and an inhibitor
ComponentsCYTOCHROME P450 3A4
KeywordsOXIDOREDUCTASE / MONOOXYGENASE / CYTOCHROME P450 / HUMAN CYP3A4 / IMIDAZOLE / 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 / IMIDAZOLE / Chem-PK9 / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 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 19, 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 1.3Dec 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

Downloads & links

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Assembly

Deposited unit
A: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,0178
Polymers55,6421
Non-polymers1,3757
Water3,423190
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.050, 99.400, 133.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-2136-

HOH

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Components

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Protein , 1 types, 1 molecules A

#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: 55641.676 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 23-503 / Mutation: YES
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

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Non-polymers , 5 types, 197 molecules

#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-PK9 / tert-butyl {6-oxo-6-[(pyridin-3-ylmethyl)amino]hexyl}carbamate


Mass: 321.415 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H27N3O3
#4: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H5N2
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O

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Details

Sequence detailsRESIDUES 3-22 DELETED MUTATIONS K282A AND E285A 4- HISTIDINE C-TERMINAL TAG

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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: 2.55 Å3/Da / Density % sol: 51.8 % / Description: NONE
Crystal growpH: 7
Details: CONDITION A3 FROM THE MORPHEUS CRYSTALLIZATION KIT (MOLECULAR DIMENSIONS), pH 7

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.127
DetectorType: ADSC CCD / Detector: CCD / Date: Jan 11, 2014 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 1.93→45 Å / Num. obs: 38419 / % possible obs: 99.2 % / Observed criterion σ(I): 2 / Redundancy: 4.9 % / Biso Wilson estimate: 37.21 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 11
Reflection shellResolution: 1.93→1.98 Å / Redundancy: 5 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 2.2 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4I3Q

4i3q


Resolution: 1.93→38.492 Å / SU ML: 0.21 / σ(F): 1.91 / Phase error: 21.16 / Stereochemistry target values: ML / Details: RESIDUES 280-288 DISORDERED
RfactorNum. reflection% reflection
Rfree0.2271 1935 5 %
Rwork0.18 --
obs0.1823 38410 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.93→38.492 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3706 0 95 190 3991
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083957
X-RAY DIFFRACTIONf_angle_d1.2555372
X-RAY DIFFRACTIONf_dihedral_angle_d15.2971518
X-RAY DIFFRACTIONf_chiral_restr0.051590
X-RAY DIFFRACTIONf_plane_restr0.006678
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9301-1.97830.2921330.2462622X-RAY DIFFRACTION100
1.9783-2.03180.26341430.20582597X-RAY DIFFRACTION100
2.0318-2.09160.21761380.19872590X-RAY DIFFRACTION100
2.0916-2.15910.23781390.19592603X-RAY DIFFRACTION100
2.1591-2.23630.2521510.192583X-RAY DIFFRACTION100
2.2363-2.32580.24281450.18662582X-RAY DIFFRACTION100
2.3258-2.43160.21851350.18212634X-RAY DIFFRACTION100
2.4316-2.55980.19061260.1932612X-RAY DIFFRACTION100
2.5598-2.72010.27491360.18992624X-RAY DIFFRACTION100
2.7201-2.93010.25061440.19032617X-RAY DIFFRACTION100
2.9301-3.22480.26381470.19542641X-RAY DIFFRACTION99
3.2248-3.69120.26541340.17532633X-RAY DIFFRACTION99
3.6912-4.64920.18061310.15252625X-RAY DIFFRACTION98
4.6492-38.49920.20591330.17822512X-RAY DIFFRACTION90
Refinement TLS params.Method: refined / Origin x: 19.4482 Å / Origin y: 25.9639 Å / Origin z: -14.6248 Å
111213212223313233
T0.2566 Å20.0029 Å20.065 Å2-0.3214 Å2-0.0082 Å2--0.2453 Å2
L1.3839 °2-1.0422 °2-0.408 °2-3.0925 °20.7016 °2--1.2556 °2
S-0.1335 Å °-0.1012 Å °-0.093 Å °0.3478 Å °0.0326 Å °-0.0458 Å °0.2531 Å °0.1306 Å °0.0983 Å °
Refinement TLS groupSelection details: ALL

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