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- PDB-5te8: Crystal structure of the midazolam-bound human CYP3A4 -

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Basic information

Entry
Database: PDB / ID: 5te8
TitleCrystal structure of the midazolam-bound human CYP3A4
ComponentsCytochrome P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE / cytochrome P450 / CYP3A4 / monooxygenase / drug metabolism / midazolam
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 / testosterone 6-beta-hydroxylase activity / vitamin D 24-hydroxylase activity / vitamin D catabolic process ...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 / testosterone 6-beta-hydroxylase activity / vitamin D 24-hydroxylase activity / vitamin D catabolic process / retinoic acid 4-hydroxylase activity / aflatoxin metabolic process / caffeine oxidase activity / estrogen 16-alpha-hydroxylase activity / estrogen 2-hydroxylase activity / lipid hydroxylation / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / : / Aflatoxin activation and detoxification / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / vitamin D metabolic process / Atorvastatin ADME / steroid catabolic process / Xenobiotics / oxidative demethylation / steroid hydroxylase activity / Phase I - Functionalization of compounds / long-chain fatty acid biosynthetic process / estrogen metabolic process / retinoic acid metabolic process / retinol metabolic process / Prednisone ADME / unspecific monooxygenase / aromatase activity / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / steroid binding / xenobiotic metabolic process / cholesterol metabolic process / monooxygenase activity / lipid metabolic process / oxygen binding / 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 / Cytochrome P450 / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-08J / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsSevrioukova, I. / Poulos, T.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)ES025767 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM57353 United States
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2017
Title: Structural basis for regiospecific midazolam oxidation by human cytochrome P450 3A4.
Authors: Sevrioukova, I.F. / Poulos, T.L.
History
DepositionSep 20, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 11, 2017Group: Database references
Revision 1.2Jan 25, 2017Group: Database references
Revision 1.3Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,1009
Polymers167,2733
Non-polymers2,8276
Water2,000111
1
A: Cytochrome P450 3A4
hetero molecules

B: Cytochrome P450 3A4
hetero molecules

C: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,1009
Polymers167,2733
Non-polymers2,8276
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_544-x,y-1/2,-z-1/21
crystal symmetry operation3_554-x,y+1/2,-z-1/21
Buried area9970 Å2
ΔGint-124 kcal/mol
Surface area54570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.289, 117.980, 205.649
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Cytochrome P450 3A4 / CYP3A4 / 1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / Albendazole sulfoxidase / CYPIIIA3 ...1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / 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 / Taurochenodeoxycholate 6-alpha-hydroxylase


Mass: 55757.812 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: human CYP3A4 with residues 3-22 deleted and the Addition C-terminal 4-histidine tag
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A4, CYP3A3 / Production host: Escherichia coli (E. coli) / Strain (production host): Bl21(DE3)
References: UniProt: P08684, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With NADH or NADPH as one donor, and incorporation of one atom of oxygen into the other donor
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-08J / 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine / Midazolam / Midazolam


Mass: 325.767 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H13ClFN3 / Comment: medication*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 111 / Source method: isolated from a natural source / Formula: H2O
Sequence detailshuman CYP3A4 with residues 3-22 deleted

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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: 2.33 Å3/Da / Density % sol: 47.24 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 12% polyethilene glycol 3350, 0.1M sodium malonate pH 7.0
PH range: 7.0-7.4

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: OXFORD TITAN CCD / Detector: CCD / Date: Jan 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→102.34 Å / Num. obs: 43549 / % possible obs: 99.4 % / Observed criterion σ(I): 2 / Redundancy: 5.6 % / CC1/2: 0.976 / Rmerge(I) obs: 0.165 / Net I/σ(I): 5.8
Reflection shellResolution: 2.7→2.8 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.822 / Mean I/σ(I) obs: 1.5 / CC1/2: 0.717 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TQN

1tqn


Resolution: 2.7→102.34 Å / Cor.coef. Fo:Fc: 0.928 / Cor.coef. Fo:Fc free: 0.883 / SU B: 39.005 / SU ML: 0.372 / Cross valid method: THROUGHOUT / ESU R Free: 0.429 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2918 2178 5 %RANDOM
Rwork0.22406 ---
obs0.22748 41161 98.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 75.677 Å2
Baniso -1Baniso -2Baniso -3
1--1.38 Å2-0 Å20 Å2
2--0.73 Å20 Å2
3---0.65 Å2
Refinement stepCycle: 1 / Resolution: 2.7→102.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11364 0 198 111 11673
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01911895
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3342.00816147
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.29351409
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.00723.828499
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.164152125
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9761566
X-RAY DIFFRACTIONr_chiral_restr0.0910.21768
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0218910
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.6754.5845645
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.8976.8717048
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.7684.6696250
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.71238.45419143
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 159 -
Rwork0.304 2999 -
obs--99.09 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.3936-0.0160.08430.30550.01740.2422-0.0276-0.0663-0.0088-0.0040.0386-0.0447-0.02040.0012-0.0110.11020.00970.02540.0744-0.0070.053116.5921-1.4558-50.9792
20.3868-0.11520.04950.8088-0.15670.5273-0.03980.0151-0.0220.18440.02960.06060.07050.08750.01020.19390.02420.03460.0530.01120.00887.206526.0069-22.0313
30.75640.1924-0.01281.5536-0.18870.0240.0706-0.00340.11120.6154-0.0851-0.1167-0.07060.01260.01450.387-0.0368-0.05390.01080.00440.032511.538-42.8746-15.2081
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A2 - 497
2X-RAY DIFFRACTION1A601 - 602
3X-RAY DIFFRACTION2B2 - 497
4X-RAY DIFFRACTION2B601 - 602
5X-RAY DIFFRACTION3C2 - 496
6X-RAY DIFFRACTION3C601 - 602

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