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- PDB-6ma7: Human CYP3A4 bound to an inhibitor fluconazole -

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Basic information

Entry
Database: PDB / ID: 6ma7
TitleHuman CYP3A4 bound to an inhibitor fluconazole
ComponentsCytochrome P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex / CYP3A4
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 / alkaloid catabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / : / 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 / cholesterol metabolic process / steroid binding / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-TPF / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.09 Å
AuthorsSevrioukova, I.F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)ES025767 United States
CitationJournal: Biochemistry / Year: 2019
Title: Interaction of Human Drug-Metabolizing CYP3A4 with Small Inhibitory Molecules.
Authors: Sevrioukova, I.
History
DepositionAug 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 16, 2019Provider: repository / Type: Initial release
Revision 1.1Jun 12, 2019Group: Data collection / Database references / Structure summary
Category: citation / citation_author / struct
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _struct.title
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)56,8235
Polymers55,7601
Non-polymers1,0634
Water1,60389
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,64510
Polymers111,5202
Non-polymers2,1268
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
2
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,29120
Polymers223,0394
Non-polymers4,25216
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_455-x-1,-y,z1
crystal symmetry operation3_455-x-1,y,-z1
crystal symmetry operation4_555x,-y,-z1
Buried area16530 Å2
ΔGint-94 kcal/mol
Surface area72650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.378, 101.310, 127.319
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 1 types, 1 molecules A

#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 / Cholesterol 25-hydroxylase / Cytochrome P450 3A3 / Cytochrome P450 HLp / Cytochrome P450 NF-25 / Cytochrome P450-PCN1 / Nifedipine oxidase / Quinine 3-monooxygenase / Taurochenodeoxycholate 6-alpha-hydroxylase


Mass: 55759.785 Da / Num. of mol.: 1 / Fragment: residues 23-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Production host: Escherichia coli (E. coli) / Strain (production host): C41
References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one ...References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor, 1,8-cineole 2-exo-monooxygenase, quinine 3-monooxygenase

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Non-polymers , 5 types, 93 molecules

#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-TPF / 2-(2,4-DIFLUOROPHENYL)-1,3-DI(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL / FLUCONAZOLE / ALPHA-(2,4-DIFLUOROPHENYL)-ALPHA-(1H-1,2,4-TRIAZOLE-1-YLMETHYL)-1H-1,2,4-TRIAZOLE-1-ETHANOL / ELAZOR / TRIFLUCAN / BIOZOLENE / Fluconazole


Mass: 306.271 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H12F2N6O / Comment: medication, antifungal*YM
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O

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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: 2.21 Å3/Da / Density % sol: 44.31 %
Crystal growTemperature: 298 K / Method: microbatch / pH: 7 / Details: PEG3350, sodium malonate

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Apr 13, 2018 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.09→79.28 Å / Num. obs: 29479 / % possible obs: 99.7 % / Redundancy: 6.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.089 / Rpim(I) all: 0.037 / Net I/σ(I): 8.7
Reflection shellResolution: 2.09→2.2 Å / Redundancy: 6.4 % / Rmerge(I) obs: 1.553 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 4228 / CC1/2: 0.412 / Rpim(I) all: 0.644 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VCC

5vcc


Resolution: 2.09→65.496 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.47
RfactorNum. reflection% reflection
Rfree0.2513 1455 4.94 %
Rwork0.1937 --
obs0.1965 29446 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.09→65.496 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3720 0 73 89 3882
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093937
X-RAY DIFFRACTIONf_angle_d1.0035340
X-RAY DIFFRACTIONf_dihedral_angle_d14.4562382
X-RAY DIFFRACTIONf_chiral_restr0.052583
X-RAY DIFFRACTIONf_plane_restr0.007674
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.16470.37111560.32442728X-RAY DIFFRACTION99
2.1647-2.25130.34141270.31582788X-RAY DIFFRACTION99
2.2513-2.35380.36481530.29782751X-RAY DIFFRACTION100
2.3538-2.47790.31941510.2782755X-RAY DIFFRACTION99
2.4779-2.63320.35931320.25512792X-RAY DIFFRACTION100
2.6332-2.83650.3131620.25232766X-RAY DIFFRACTION100
2.8365-3.12190.3181450.24412781X-RAY DIFFRACTION99
3.1219-3.57360.31881450.21142799X-RAY DIFFRACTION99
3.5736-4.50230.20611410.1592866X-RAY DIFFRACTION100
4.5023-65.52860.18681430.15232965X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -18.9359 Å / Origin y: -23.8698 Å / Origin z: -12.6772 Å
111213212223313233
T0.339 Å20.0142 Å20.0037 Å2-0.5328 Å2-0.0947 Å2--0.4272 Å2
L3.9577 °2-2.3939 °2-0.4661 °2-5.9893 °20.5137 °2--2.7829 °2
S0.0416 Å °0.3753 Å °-0.1925 Å °-0.0552 Å °-0.1035 Å °-0.0832 Å °0.2826 Å °0.1877 Å °0.0338 Å °
Refinement TLS groupSelection details: all

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