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- PDB-4i4g: Crystal structure of CYP3A4 ligated to oxazole-substituted desoxy... -

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Basic information

Entry
Database: PDB / ID: 4i4g
TitleCrystal structure of CYP3A4 ligated to oxazole-substituted desoxyritonavir
ComponentsCytochrome P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / monooxygenase / cytochrome P450 reductase / cytochrome b5 / endoplasmic reticulum / cytochrome P450 / 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 / 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 / alkaloid catabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / : / 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 / cholesterol metabolic process / steroid binding / xenobiotic 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-Z8Z / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.718 Å
AuthorsSevrioukova, I.F. / Poulos, T.L.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir.
Authors: Sevrioukova, I.F. / Poulos, T.L.
History
DepositionNov 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2013Provider: repository / Type: Initial release
Revision 1.1May 1, 2013Group: Database references
Revision 1.2May 22, 2013Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,0633
Polymers55,7581
Non-polymers1,3052
Water905
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules

A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,25312
Polymers223,0314
Non-polymers5,2218
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
crystal symmetry operation3_555-x,y,-z1
crystal symmetry operation4_555x,-y,-z1
Buried area7170 Å2
ΔGint-57 kcal/mol
Surface area74970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.655, 99.585, 126.375
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 / CYP3A4 / 1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / Albendazole sulfoxidase / CYPIIIA3 ...1 / 8-cineole 2-exo-monooxygenase / Albendazole monooxygenase / Albendazole sulfoxidase / CYPIIIA3 / CYPIIIA4 / 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.: 1 / Mutation: residues 3-22 deleted
Source method: isolated from a genetically manipulated source
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 ...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, EC: 1.14.13.157, EC: 1.14.13.32, EC: 1.14.13.67, EC: 1.14.13.97
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-Z8Z / N~2~-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-N-[(2R,5R)-5-{[(1,3-oxazol-5-ylmethoxy)carbonyl]amino}-1,6-diphenylhexan-2-yl]-L-valinamide


Mass: 688.879 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H48N6O5S
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O

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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: 2.16 Å3/Da / Density % sol: 43.13 %
Crystal growTemperature: 298 K / Method: microbatch under oil / pH: 6
Details: PEG 3350, sodium malonate, pH 6.0, microbatch under oil, temperature 298K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.127 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 12, 2012 / Details: mirrors
RadiationMonochromator: Yale mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 2.718→49.8 Å / Num. all: 12248 / Num. obs: 12236 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 9.4 % / Rmerge(I) obs: 0.072 / Net I/σ(I): 18.9
Reflection shellResolution: 2.718→2.79 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.505 / Mean I/σ(I) obs: 3.5 / Num. unique all: 845 / % possible all: 98.9

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3NXU

3nxu


Resolution: 2.718→49.79 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.907 / SU B: 32.958 / SU ML: 0.312 / Cross valid method: THROUGHOUT / σ(I): 2 / ESU R Free: 0.408 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.26971 661 4.9 %RANDOM
Rwork0.2034 ---
obs0.20661 12710 99.82 %-
all-12733 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 91.946 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å20 Å20 Å2
2---0.04 Å20 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 2.718→49.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3695 0 92 5 3792
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.023886
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8942.0175270
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2815456
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.7423.851161
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.59215690
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.2941522
X-RAY DIFFRACTIONr_chiral_restr0.0920.2580
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212901
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.718→2.789 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 36 -
Rwork0.262 863 -
obs--99.01 %
Refinement TLS params.Method: refined / Origin x: -19.0826 Å / Origin y: 23.6054 Å / Origin z: -12.6565 Å
111213212223313233
T0.1028 Å2-0.0178 Å2-0.0311 Å2-0.1798 Å20.0631 Å2--0.1081 Å2
L1.5506 °2-1.0947 °20.2718 °2-4.0551 °2-0.6635 °2--1.9179 °2
S-0.1527 Å °0.0648 Å °0.2591 Å °0.546 Å °0.0659 Å °-0.2421 Å °-0.3008 Å °0.0871 Å °0.0867 Å °

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