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- PDB-9gk1: SSX structure of human cytochrome P450 3A4 at room temperature -

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Basic information

Entry
Database: PDB / ID: 9gk1
TitleSSX structure of human cytochrome P450 3A4 at room temperature
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE / monooxygenase
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 / long-chain fatty acid biosynthetic process / unspecific monooxygenase / 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 / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.95 Å
AuthorsGlerup, J. / Branden, G. / Uwangue, O.
Funding support Sweden, 4items
OrganizationGrant numberCountry
Swedish Research Council2017-06734 Sweden
Swedish Research Council2021-05662 Sweden
Swedish Research Council2021-05981 Sweden
The Swedish Foundation for Strategic ResearchID17-0060 Sweden
CitationJournal: Arch.Biochem.Biophys. / Year: 2025
Title: Microcrystallization and room-temperature serial crystallography structure of human cytochrome P450 3A4.
Authors: Uwangue, O. / Glerup, J. / Dunge, A. / Bjelcic, M. / Wehlander, G. / Branden, G.
History
DepositionAug 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 7, 2025Provider: repository / Type: Initial release

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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)55,9672
Polymers55,3501
Non-polymers6161
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS, Crystal is formed by monomers, determined by SAXS to form a tetramer in solution.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-22 kcal/mol
Surface area19880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.950, 103.740, 128.640
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: 55350.289 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Organ: Liver / Production host: Escherichia coli BL21 (bacteria)
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 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O
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: 2.41 Å3/Da / Density % sol: 48.95 % / Description: Square rods
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7.3
Details: Final droplet contained 6%v/v PEG3350, 50 mM sodium malonate, 15 mg/mL CYP3A4, 25 mM KPi pH 7.3, 100 mM KCl, 1 mM DTT, 0.5 mM EDTA, 10%v/v glycerol, 1%v/v DMSO and 100 uM beta-napthoflavone. ...Details: Final droplet contained 6%v/v PEG3350, 50 mM sodium malonate, 15 mg/mL CYP3A4, 25 mM KPi pH 7.3, 100 mM KCl, 1 mM DTT, 0.5 mM EDTA, 10%v/v glycerol, 1%v/v DMSO and 100 uM beta-napthoflavone. The droplet was equillibrated against a reservoir of 100 mM sodium malonate and 12%v/v PEG3350. The crystalisation droplet swelled due to high glycerol concentration.

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Data collection

DiffractionMean temperature: 293 K / Serial crystal experiment: Y
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.976 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 9, 2022
Details: BioMAX components: undulator, two front-end beam position monitors, front-end fluorescent screen, optics hutch fixed mask, double-crystal monochromator, fluorescent screen, NanoBPM, slits, ...Details: BioMAX components: undulator, two front-end beam position monitors, front-end fluorescent screen, optics hutch fixed mask, double-crystal monochromator, fluorescent screen, NanoBPM, slits, vertical focusing mirror, horizontal focusing mirror, NanoBPM, beam conditioning unit (BCU), sample and detector. The BCU chamber includes slits, diagnostics, two diamond beam position monitors, attenuators, shutter, slits and diagnostics.
RadiationMonochromator: Si (111) horizontal double crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.95→80.75 Å / Num. obs: 11603 / % possible obs: 100 % / Redundancy: 416.91 % / Biso Wilson estimate: 121.39 Å2 / CC1/2: 0.9953922 / CC star: 0.9988447 / R split: 0.0543 / Net I/σ(I): 14.758752
Reflection shellResolution: 2.95→3 Å / Redundancy: 282.9 % / Mean I/σ(I) obs: 1 / Num. unique obs: 547 / CC1/2: 0.5453646 / CC star: 0.8401232 / R split: 0.7304 / % possible all: 100
Serial crystallography measurementCollection time total: 2 hours / Collimation: Kirkpatrick-Baez mirror pair
Serial crystallography sample deliveryDescription: Serial X SPINE-mounted Kapton membrane sandwich on a plastic frame
Method: fixed target
Serial crystallography sample delivery fixed targetDescription: 8 x 1 uL crystal slurry on kapton films
Details: Arinax Microdiffractomer MD3-down mini-kappagoniometer head
Motion control: Arinax Microdiffractomer MD3-down
Sample dehydration prevention: Encapsulated by kapton film and glue
Sample holding: Serial X SPINE-mounted Kapton membrane sandwich on a plastic frame
Support base: SPINE-compatible
Serial crystallography data reductionFrames indexed: 52670 / Frames total: 169142 / Lattices indexed: 66748

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
CrystFEL0.10.1-6data scaling
CrystFEL0.10.1-6data reduction
PHASER2.8.3phasing
Coot0.9.8.92model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.95→80.75 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.94 / SU B: 65.754 / SU ML: 0.524 / Cross valid method: THROUGHOUT / ESU R Free: 0.519 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.29508 589 5.1 %RANDOM
Rwork0.24369 ---
obs0.24643 11009 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 143.605 Å2
Baniso -1Baniso -2Baniso -3
1--1.74 Å2-0 Å20 Å2
2--0.1 Å2-0 Å2
3---1.64 Å2
Refinement stepCycle: 1 / Resolution: 2.95→80.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3738 0 43 2 3783
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0133878
X-RAY DIFFRACTIONr_bond_other_d0.0010.0153771
X-RAY DIFFRACTIONr_angle_refined_deg1.2081.6695259
X-RAY DIFFRACTIONr_angle_other_deg0.9751.5878715
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.6825461
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.47422.204186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.10515698
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.9771522
X-RAY DIFFRACTIONr_chiral_restr0.0350.2493
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.024253
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02871
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.57310.3981853
X-RAY DIFFRACTIONr_mcbond_other0.57310.3971852
X-RAY DIFFRACTIONr_mcangle_it1.06915.5892311
X-RAY DIFFRACTIONr_mcangle_other1.06915.5892312
X-RAY DIFFRACTIONr_scbond_it0.31910.3792024
X-RAY DIFFRACTIONr_scbond_other0.31910.3812022
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.93915.5352948
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.95→3.027 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.454 43 -
Rwork0.393 791 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: -20.331 Å / Origin y: -24.132 Å / Origin z: -13.432 Å
111213212223313233
T0.1421 Å20.0375 Å20.0624 Å2-0.068 Å2-0.0232 Å2--0.1301 Å2
L3.9801 °2-1.5181 °2-0.9572 °2-4.9795 °20.974 °2--2.6633 °2
S0.0898 Å °0.3009 Å °-0.4567 Å °-0.0277 Å °-0.1837 Å °-0.2245 Å °0.2071 Å °0.2403 Å °0.0939 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A28 - 497
2X-RAY DIFFRACTION1A601

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