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- PDB-9ms1: Crystal structure of human CYP3A4 in complex with SJYHJ-111 -

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Basic information

Entry
Database: PDB / ID: 9ms1
TitleCrystal structure of human CYP3A4 in complex with SJYHJ-111
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/INHIBITOR / Cytochrome P450 3A4 / CYP3A4 / CYP3A4-selective inhibitor / drug metabolizing enzyme / 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 / aflatoxin metabolic process / caffeine oxidase activity / lipid hydroxylation / testosterone 6-beta-hydroxylase activity / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / Aflatoxin activation and detoxification / estrogen 16-alpha-hydroxylase activity / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / vitamin D metabolic process / estrogen 2-hydroxylase activity / oxidative demethylation / steroid catabolic process / Atorvastatin ADME / steroid hydroxylase activity / Xenobiotics / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / retinoic acid metabolic process / retinol metabolic process / estrogen metabolic process / unspecific monooxygenase / Prednisone ADME / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / steroid binding / xenobiotic metabolic process / cholesterol 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 / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsJingheng, W. / Nithianantham, S. / Miller, D.J. / Chen, T.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM118041 United States
CitationJournal: Nat Commun / Year: 2025
Title: Decoding the selective chemical modulation of CYP3A4.
Authors: Wang, J. / Nithianantham, S. / Chai, S.C. / Jung, Y.H. / Yang, L. / Ong, H.W. / Li, Y. / Zhang, Y. / Miller, D.J. / Chen, T.
History
DepositionJan 9, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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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)56,6983
Polymers55,5951
Non-polymers1,1032
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)75.772, 100.654, 121.133
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: 55594.637 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: First residues (M) - Initiating methionine Second residue (A) - Expression Tag Last 4 residues (HHHH) - Expression Tag Missing residues (DGTVGA)
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Plasmid: pCWori / Production host: Escherichia coli (E. coli) / Strain (production host): DH5alpha
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: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-A1BNX / N'-(2-chlorophenyl)-N-[(3-hydroxyphenyl)methyl]-N-[(2P)-2-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]urea


Mass: 486.874 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18ClF3N4O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: 2.08 Å3/Da / Density % sol: 40.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 0.1 M HEPES, pH 7.0, 10-12% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92012 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 18, 2024
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92012 Å / Relative weight: 1
ReflectionResolution: 3.4→30.27 Å / Num. obs: 6641 / % possible obs: 99.8 % / Redundancy: 5.7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.16 / Rpim(I) all: 0.078 / Rrim(I) all: 0.192 / Χ2: 1.08 / Net I/av σ(I): 6.4 / Net I/σ(I): 6.4
Reflection shellResolution: 3.4→3.67 Å / Redundancy: 5.6 % / Rmerge(I) obs: 1.598 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 1348 / CC1/2: 0.655 / Rpim(I) all: 0.716 / Rrim(I) all: 1.76 / Χ2: 1.06

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487)refinement
Aimlessdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.4→30.27 Å / SU ML: 0.44 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 35.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.297 334 5.08 %
Rwork0.2841 --
obs0.2849 6575 98.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.4→30.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3086 0 77 0 3163
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043249
X-RAY DIFFRACTIONf_angle_d0.6684485
X-RAY DIFFRACTIONf_dihedral_angle_d11.8871021
X-RAY DIFFRACTIONf_chiral_restr0.049510
X-RAY DIFFRACTIONf_plane_restr0.012595
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.4-3.520.4812400.3728611X-RAY DIFFRACTION100
3.52-3.660.363320.3514615X-RAY DIFFRACTION100
3.66-3.830.3273330.327618X-RAY DIFFRACTION100
3.83-4.030.3406310.3351626X-RAY DIFFRACTION100
4.03-4.280.3446330.3068617X-RAY DIFFRACTION100
4.28-4.610.3301360.3229630X-RAY DIFFRACTION99
5.07-5.80.3355340.3183619X-RAY DIFFRACTION97
5.8-7.290.3201310.2932624X-RAY DIFFRACTION97
7.3-30.270.2357350.1971660X-RAY DIFFRACTION97

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