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- PDB-6unm: CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 6unm
TitleCYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / CYP3A4 / inhibitor / complex / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR 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-QDP / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.83 Å
AuthorsSevrioukova, I.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)ES025767 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2020
Title: An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.
Authors: Samuels, E.R. / Sevrioukova, I.F.
History
DepositionOct 12, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2020Group: Derived calculations
Category: pdbx_struct_assembly / pdbx_struct_assembly_gen ...pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_oper_list
Item: _pdbx_struct_assembly_prop.biol_id / _pdbx_struct_assembly_prop.value
Revision 1.2Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Mar 4, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.4Oct 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
B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,3665
Polymers111,5162
Non-polymers1,8513
Water00
1
B: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,7494
Polymers111,5162
Non-polymers1,2332
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_657-x+1,y,-z+21
2
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,9846
Polymers111,5162
Non-polymers2,4694
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area3470 Å2
ΔGint-55 kcal/mol
Surface area38200 Å2
MethodPISA
3
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,73310
Polymers223,0314
Non-polymers3,7026
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
crystal symmetry operation3_454x-1/2,y+1/2,z-11
crystal symmetry operation4_556-x+1/2,y+1/2,-z+11
Buried area10280 Å2
ΔGint-149 kcal/mol
Surface area72390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)149.530, 97.910, 92.300
Angle α, β, γ (deg.)90.000, 123.570, 90.000
Int Tables number5
Space group name H-MC121

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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 / 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: 55757.812 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): C41
References: UniProt: P08684, unspecific monooxygenase, 1,8-cineole 2-exo-monooxygenase, albendazole monooxygenase (sulfoxide-forming), quinine 3-monooxygenase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-QDP / tert-butyl [(2S)-1-(naphthalen-1-yl)-3-{[(2S)-3-(naphthalen-1-yl)-1-oxo-1-{(E)-[2-(pyridin-3-yl)ethylidene]amino}propan-2-yl]sulfanyl}propan-2-yl]carbamate


Mass: 617.800 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H39N3O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.52 Å3/Da / Density % sol: 51.27 %
Crystal growTemperature: 298 K / Method: microbatch / Details: PEG 3350, sodium malonate / PH range: 6.0-7.0

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 19, 2018 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.83→76.98 Å / Num. obs: 25711 / % possible obs: 97 % / Redundancy: 4.5 % / Biso Wilson estimate: 104.58 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rpim(I) all: 0.035 / Rrim(I) all: 0.077 / Net I/σ(I): 8.9 / Num. measured all: 115703
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.83-2.984.51.6881687637750.3880.8851.9160.897.3
8.95-76.984.30.03436568450.9990.0190.03929.296.9

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Processing

Software
NameVersionClassification
SCALAdata scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5VCC

5vcc


Resolution: 2.83→62.295 Å / SU ML: 0.54 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 37.09
RfactorNum. reflection% reflection
Rfree0.2818 1191 4.64 %
Rwork0.2306 --
obs0.2329 25653 96.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 374.5 Å2 / Biso mean: 153.6147 Å2 / Biso min: 46.3 Å2
Refinement stepCycle: final / Resolution: 2.83→62.295 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6920 0 131 0 7051
Biso mean--108.68 --
Num. residues----864
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067266
X-RAY DIFFRACTIONf_angle_d0.8849864
X-RAY DIFFRACTIONf_chiral_restr0.0461084
X-RAY DIFFRACTIONf_plane_restr0.0071240
X-RAY DIFFRACTIONf_dihedral_angle_d15.5274376
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.83-2.94330.42341040.4052274997
2.9433-3.07730.40381410.3611263995
3.0773-3.23950.39281430.3248260994
3.2395-3.44250.32991120.293279199
3.4425-3.70820.33171350.2816274198
3.7082-4.08130.29361220.2438270595
4.0813-4.67180.27441380.2142273798
4.6718-5.88520.28491650.2306272097
5.8852-62.2950.22781310.1852277196
Refinement TLS params.Method: refined / Origin x: 24.1724 Å / Origin y: -25.6182 Å / Origin z: 30.3904 Å
111213212223313233
T0.6634 Å2-0.0673 Å2-0.0534 Å2-0.5685 Å20.0889 Å2--0.6214 Å2
L0.6268 °2-0.3681 °20.2522 °2-0.4376 °2-0.9327 °2--1.6995 °2
S-0.0645 Å °-0.0634 Å °-0.0375 Å °0.2424 Å °-0.0586 Å °-0.2751 Å °-0.2619 Å °-0.035 Å °0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA28 - 700
2X-RAY DIFFRACTION1allB29 - 495
3X-RAY DIFFRACTION1allB500

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