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

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Basic information

Entry
Database: PDB / ID: 7uff
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-NYF / PHOSPHATE ION / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 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)113,8037
Polymers111,2832
Non-polymers2,5195
Water23413
1
A: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,8037
Polymers111,2832
Non-polymers2,5195
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_756-x+5/2,y+1/2,-z+11
Unit cell
Length a, b, c (Å)156.618, 97.879, 95.149
Angle α, β, γ (deg.)90.00, 125.20, 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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-NYF / N-(2-oxo-2-{[(2S)-1-{[(2R)-1-oxo-3-phenyl-1-{[3-(pyridin-3-yl)propyl]amino}propan-2-yl]sulfanyl}-3-phenylpropan-2-yl]amino}ethyl)pyridine-3-carboxamide


Mass: 595.754 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H37N5O3S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / 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: 2.91 Å3/Da / Density % sol: 57.66 %
Crystal growTemperature: 298 K / Method: microbatch / Details: PEG 3350, sodium succinate pH 7.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 16, 2021 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.7→77.75 Å / Num. obs: 30683 / % possible obs: 95.1 % / Redundancy: 6 % / Biso Wilson estimate: 83 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.115 / Rpim(I) all: 0.05 / Net I/σ(I): 8.5
Reflection shellResolution: 2.7→2.85 Å / Rmerge(I) obs: 1.774 / Mean I/σ(I) obs: 1 / Num. unique obs: 4113 / CC1/2: 0.405 / Rpim(I) all: 0.818 / % possible all: 88.6

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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: 2.7→47.54 Å / SU ML: 0.51 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 33.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2811 1472 4.81 %
Rwork0.2437 --
obs0.2454 30631 94.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.7→47.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7205 0 177 13 7395
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0027637
X-RAY DIFFRACTIONf_angle_d0.51110345
X-RAY DIFFRACTIONf_dihedral_angle_d12.3234595
X-RAY DIFFRACTIONf_chiral_restr0.0381134
X-RAY DIFFRACTIONf_plane_restr0.0031302
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.78710.41881320.39782467X-RAY DIFFRACTION88
2.7871-2.88670.40441280.35862544X-RAY DIFFRACTION92
2.8867-3.00230.39851330.33492703X-RAY DIFFRACTION98
3.0023-3.13890.33481290.29862743X-RAY DIFFRACTION98
3.1389-3.30440.30611520.30532694X-RAY DIFFRACTION97
3.3044-3.51130.32151310.29612714X-RAY DIFFRACTION97
3.5113-3.78230.31161050.27232503X-RAY DIFFRACTION89
3.7823-4.16280.31461590.24362715X-RAY DIFFRACTION98
4.1628-4.76460.2531190.21772755X-RAY DIFFRACTION97
4.7646-6.00110.25361330.22342570X-RAY DIFFRACTION92
6.0011-47.540.2291510.19892751X-RAY DIFFRACTION96
Refinement TLS params.Method: refined / Origin x: 181.4341 Å / Origin y: -21.9628 Å / Origin z: 30.5524 Å
111213212223313233
T0.4006 Å2-0.0005 Å2-0.0218 Å2-0.4468 Å20.066 Å2--0.4425 Å2
L0.2235 °20.1097 °20.1505 °2-0.6101 °2-0.4316 °2--1.2707 °2
S-0.0117 Å °-0.1443 Å °-0.0034 Å °0.2471 Å °-0.0687 Å °-0.1662 Å °-0.1449 Å °0.1318 Å °-0.0113 Å °
Refinement TLS groupSelection details: all

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