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- PDB-7ufe: Human CYP3A4 bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 7ufe
TitleHuman CYP3A4 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-NXR / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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: 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

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)113,8709
Polymers111,2832
Non-polymers2,5877
Water95553
1
A: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,8709
Polymers111,2832
Non-polymers2,5877
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_758-x+5/2,y+1/2,-z+31
Unit cell
Length a, b, c (Å)153.617, 96.749, 93.869
Angle α, β, γ (deg.)90.00, 124.21, 90.00
Int Tables number5
Space group name H-MC121

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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: 55641.609 Da / Num. of mol.: 2 / Mutation: residues 3-22 deleted, K421A and K424A mutations
Source method: isolated from a genetically manipulated source
Details: C-terminal 4-histidine tag / 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.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-NXR / N-[(2S)-1-{[(2R)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]pyridine-3-carboxamide


Mass: 538.703 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H34N4O2S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / Source method: isolated from a natural source / Formula: H2O
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: 2.79 Å3/Da / Density % sol: 55.88 %
Crystal growTemperature: 298 K / Method: microbatch / Details: PEG 3350, tacsimate pH 6.5

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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: Jun 1, 2021 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.4→77.63 Å / Num. obs: 43861 / % possible obs: 98.7 % / Redundancy: 3.4 % / Biso Wilson estimate: 71 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.039 / Net I/σ(I): 8.3
Reflection shellResolution: 2.4→2.53 Å / Rmerge(I) obs: 1.257 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 6382 / CC1/2: 0.506 / Rpim(I) all: 0.777 / % possible all: 98.9

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7kvh, molecule A

7kvh


Resolution: 2.4→48.375 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 34.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2534 2117 4.84 %
Rwork0.221 --
obs0.2226 43781 98.36 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→48.375 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7268 0 182 53 7503
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027678
X-RAY DIFFRACTIONf_angle_d0.50310390
X-RAY DIFFRACTIONf_dihedral_angle_d12.6914623
X-RAY DIFFRACTIONf_chiral_restr0.0381137
X-RAY DIFFRACTIONf_plane_restr0.0041304
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.45580.4241580.36222736X-RAY DIFFRACTION98
2.4558-2.51720.37261590.35632736X-RAY DIFFRACTION98
2.5172-2.58530.36171610.31922740X-RAY DIFFRACTION98
2.5853-2.66140.35041160.31132784X-RAY DIFFRACTION98
2.6614-2.74730.40051130.30092816X-RAY DIFFRACTION99
2.7473-2.84540.31071370.29632711X-RAY DIFFRACTION97
2.8454-2.95940.3321010.28762819X-RAY DIFFRACTION98
2.9594-3.0940.30891190.27152769X-RAY DIFFRACTION99
3.094-3.25710.31521210.26912852X-RAY DIFFRACTION99
3.2571-3.46110.27411430.25962770X-RAY DIFFRACTION99
3.4611-3.72830.29591500.24662748X-RAY DIFFRACTION98
3.7283-4.10330.25841740.20932797X-RAY DIFFRACTION100
4.1033-4.69660.22021500.18552777X-RAY DIFFRACTION99
4.6966-5.91550.2311850.19422740X-RAY DIFFRACTION98
5.9155-48.3750.18831300.17812869X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 125.4397 Å / Origin y: -21.755 Å / Origin z: 108.2844 Å
111213212223313233
T0.4628 Å20.0018 Å2-0.0113 Å2-0.5313 Å20.0371 Å2--0.5641 Å2
L0.7275 °2-0.0764 °20.0865 °2-1.0828 °2-0.9362 °2--2.4645 °2
S-0.0277 Å °-0.2123 Å °-0.0107 Å °0.2932 Å °-0.0002 Å °-0.0068 Å °-0.2115 Å °0.0203 Å °0.0126 Å °
Refinement TLS groupSelection details: all

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