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- PDB-7uf9: CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 7uf9
TitleCYP3A4 bound to an inhibitor
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/INHIBITOR / CYP3A4 / inhibitor / complex / 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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity ...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 / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / lipid hydroxylation / aflatoxin metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / testosterone 6-beta-hydroxylase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / vitamin D metabolic process / steroid catabolic process / Atorvastatin ADME / steroid hydroxylase activity / Xenobiotics / Phase I - Functionalization of compounds / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / unspecific monooxygenase / long-chain fatty acid biosynthetic process / Prednisone ADME / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / cholesterol metabolic process / steroid binding / xenobiotic metabolic process / monooxygenase activity / oxygen binding / lipid metabolic process / 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, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-NH0 / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 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: Int J Mol Sci / Year: 2022
Title: Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment.
Authors: Samuels, E.R. / Sevrioukova, I.F.
History
DepositionMar 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 27, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)56,8943
Polymers55,7581
Non-polymers1,1362
Water00
1
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,7886
Polymers111,5162
Non-polymers2,2724
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_545x,-y-1,-z1
Unit cell
Length a, b, c (Å)76.730, 101.420, 128.180
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 / 4-cineole 2-exo-monooxygenase / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase ...1 / 4-cineole 2-exo-monooxygenase / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase (sulfoxide-forming) / 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


Mass: 55757.812 Da / Num. of mol.: 1 / Mutation: residues 3-22 deleted, C-terminal 4-histidine tag
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Production host: Escherichia coli BL21(DE3) (bacteria) / 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.: 1
Source method: isolated from a genetically manipulated source
Formula: C34H32FeN4O4
#3: Chemical ChemComp-NH0 / tert-butyl [(2S)-1-{[(2R)-1-oxo-3-phenyl-1-{[2-(pyridin-4-yl)ethyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]carbamate


Mass: 519.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H37N3O3S / 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: 2.24 Å3/Da / Density % sol: 45 %
Crystal growTemperature: 298 K / Method: microbatch / Details: PEG 3350, taximate pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Nov 19, 2017 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.45→79.53 Å / Num. obs: 18319 / % possible obs: 98.1 % / Redundancy: 4.5 % / Biso Wilson estimate: 85 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.024 / Net I/σ(I): 12.5
Reflection shellResolution: 2.45→2.58 Å / Rmerge(I) obs: 1.63 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2694 / CC1/2: 0.416 / Rpim(I) all: 0.842

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5vcc

5vcc


Resolution: 2.45→44.258 Å / SU ML: 0.53 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 36.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2551 879 4.81 %
Rwork0.2254 --
obs0.2268 18268 97.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.45→44.258 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3548 0 80 0 3628
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043747
X-RAY DIFFRACTIONf_angle_d0.6345083
X-RAY DIFFRACTIONf_dihedral_angle_d13.992262
X-RAY DIFFRACTIONf_chiral_restr0.04559
X-RAY DIFFRACTIONf_plane_restr0.005637
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.60350.44751460.36642879X-RAY DIFFRACTION99
2.6035-2.80450.3461580.32662802X-RAY DIFFRACTION96
2.8045-3.08660.42931420.29432901X-RAY DIFFRACTION98
3.0866-3.53310.34821180.27672957X-RAY DIFFRACTION99
3.5331-4.45070.24621420.22562894X-RAY DIFFRACTION97
4.4507-44.2580.21531730.18942956X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: -19.3484 Å / Origin y: -27.2261 Å / Origin z: -13.51 Å
111213212223313233
T0.4839 Å2-0.0051 Å2-0.0576 Å2-0.5743 Å20.0612 Å2--0.5178 Å2
L1.9831 °2-1.5921 °20.5484 °2-4.2077 °2-0.7507 °2--2.1976 °2
S-0.0051 Å °0.2167 Å °0.0496 Å °0.0839 Å °-0.0605 Å °0.1886 Å °-0.1629 Å °-0.1351 Å °-0.0001 Å °
Refinement TLS groupSelection details: all

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