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- PDB-4d75: Cytochrome P450 3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 4d75
TitleCytochrome P450 3A4 bound to an inhibitor
ComponentsCYTOCHROME P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE / MONOOXYGENASE / 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 / steroid catabolic process / Xenobiotics / oxidative demethylation / steroid hydroxylase activity / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinoic acid metabolic process / retinol metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / steroid binding / xenobiotic metabolic process / cholesterol 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-PK9 / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 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 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
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)56,5803
Polymers55,6421
Non-polymers9382
Water30617
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.090, 99.750, 131.450
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 / CYP3A4 / 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, 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
#2: 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
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 17 / Source method: isolated from a natural source / Formula: H2O
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: 2.53 Å3/Da / Density % sol: 51.4 % / Description: NONE
Crystal growMethod: vapor diffusion, sitting drop / pH: 7
Details: VAPOR DIFFUSION SITTING DROP AGAINST 80% OF THE E3 SOLUTION FROM MORPHEUS CRYSTALLIZATION KIT (MOLECULAR DIMENSIONS), PH 7

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1
DetectorDate: Sep 20, 2014 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.25→79.5 Å / Num. obs: 24435 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 5.7 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 9.9
Reflection shellResolution: 2.25→2.32 Å / Redundancy: 5.8 % / Rmerge(I) obs: 1.12 / Mean I/σ(I) obs: 1.3 / % 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 4D6Z

4d6z


Resolution: 2.25→79.461 Å / SU ML: 0.29 / σ(F): 1.34 / Phase error: 29.33 / Stereochemistry target values: ML / Details: RESIDUES 263-266 AND 282-286 DISORDERED
RfactorNum. reflection% reflection
Rfree0.254 1245 5.1 %
Rwork0.2 --
obs0.2028 24385 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.25→79.461 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3708 0 66 17 3791
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123921
X-RAY DIFFRACTIONf_angle_d1.6615317
X-RAY DIFFRACTIONf_dihedral_angle_d16.2691493
X-RAY DIFFRACTIONf_chiral_restr0.06583
X-RAY DIFFRACTIONf_plane_restr0.008671
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2501-2.34020.32361330.29322556X-RAY DIFFRACTION100
2.3402-2.44680.28611320.2752521X-RAY DIFFRACTION100
2.4468-2.57580.30781380.25542558X-RAY DIFFRACTION100
2.5758-2.73720.30011350.25092541X-RAY DIFFRACTION100
2.7372-2.94850.35871420.24782553X-RAY DIFFRACTION100
2.9485-3.24520.29331450.24142555X-RAY DIFFRACTION100
3.2452-3.71480.28151490.21552555X-RAY DIFFRACTION100
3.7148-4.68020.21121390.16782583X-RAY DIFFRACTION99
4.6802-79.51090.211320.16452718X-RAY DIFFRACTION99
Refinement TLS params.Method: refined / Origin x: -18.9348 Å / Origin y: -23.8528 Å / Origin z: -13.5899 Å
111213212223313233
T0.3392 Å2-0.0141 Å20.0599 Å2-0.3589 Å2-0.0229 Å2--0.332 Å2
L1.0163 °2-0.9483 °2-0.3338 °2-2.4469 °20.618 °2--1.0086 °2
S-0.1051 Å °-0.0112 Å °-0.0386 Å °0.2634 Å °-0.0569 Å °0.0333 Å °0.1624 Å °0.0127 Å °-0.0089 Å °
Refinement TLS groupSelection details: ALL

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