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- PDB-3nxu: Crystal structure of human cytochrome P4503A4 bound to an inhibit... -

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Basic information

Entry
Database: PDB / ID: 3nxu
TitleCrystal structure of human cytochrome P4503A4 bound to an inhibitor ritonavir
ComponentsCytochrome P450 3A4CYP3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / alpha beta protein / cytochrome P450 fold / hemoprotein / monooxygenase / cytochrome P450 reductase / endoplasmic reticulum / 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 / 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
RITONAVIR / PROTOPORPHYRIN IX CONTAINING FE / RITONAVIR / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsSevrioukova, I.F. / Poulos, T.L.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2010
Title: Structure and mechanism of the complex between cytochrome P4503A4 and ritonavir.
Authors: Sevrioukova, I.F. / Poulos, T.L.
History
DepositionJul 14, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 20, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Sep 6, 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_asym_id / _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_asym_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
Remark 999THIS PROTEIN CONSISTS OF UNP RESIDUES 1-2 AND 25-503. DUE TO A DELETION OF UNP RESIDUES 3-24, ...THIS PROTEIN CONSISTS OF UNP RESIDUES 1-2 AND 25-503. DUE TO A DELETION OF UNP RESIDUES 3-24, RESIDUES 23-24 (MET ALA) IN 3NXU CORRESPONDING TO UNP RESIDUE 1-2.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cytochrome P450 3A4
B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,10712
Polymers110,9632
Non-polymers3,14410
Water7,008389
1
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,1317
Polymers55,4811
Non-polymers1,6506
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9755
Polymers55,4811
Non-polymers1,4944
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)162.123, 94.690, 93.130
Angle α, β, γ (deg.)90.00, 124.25, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Cytochrome P450 3A4 / CYP3A4 / Quinine 3-monooxygenase / CYPIIIA4 / Nifedipine oxidase / Cytochrome P450 3A3 / CYPIIIA3 / ...Quinine 3-monooxygenase / CYPIIIA4 / Nifedipine oxidase / Cytochrome P450 3A3 / CYPIIIA3 / Cytochrome P450 HLp / Taurochenodeoxycholate 6-alpha-hydroxylase / Cytochrome P450 NF-25 / Cytochrome P450-PCN1 / Albendazole monooxygenase / Albendazole sulfoxidase


Mass: 55481.480 Da / Num. of mol.: 2 / Fragment: UNP residues 1-2 and 25-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP3A3, CYP3A4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P08684, EC: 1.14.13.67, EC: 1.14.13.97, EC: 1.14.13.32
#2: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Chemical ChemComp-RIT / RITONAVIR / / A-84538 / Ritonavir


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 720.944 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C37H48N6O5S2 / References: RITONAVIR / Comment: medication, antiretroviral*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 389 / 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: 2.66 Å3/Da / Density % sol: 53.8 %
Crystal growTemperature: 293 K / Method: microbatch under oil / pH: 6
Details: 100 mM sodium malonate pH 6.0, 12 % polyethylene glycol 3350, microbatch under oil, temperature 293K

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Data collection

DiffractionMean temperature: 103 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 1 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Details: mirrors
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→77.38 Å / Num. all: 78378 / Num. obs: 76811 / % possible obs: 98 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.7 % / Biso Wilson estimate: 34.8 Å2 / Rmerge(I) obs: 0.064 / Net I/σ(I): 10.8
Reflection shellResolution: 2→2.05 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.35 / Mean I/σ(I) obs: 4.6 / Num. unique all: 21094 / % possible all: 97.4

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Processing

Software
NameClassification
Blu-Icedata collection
PHASERphasing
CNSrefinement
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TQN

1tqn


Resolution: 2→40.4 Å / Isotropic thermal model: overall / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.262 3889 -random
Rwork0.232 ---
all0.264 78695 --
obs0.235 76649 97.4 %-
Displacement parametersBiso mean: 44.3 Å2
Baniso -1Baniso -2Baniso -3
1-9.8 Å2-7.9 Å2-1.89 Å2
2--0 Å2-5.44 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.35 Å0.3 Å
Luzzati d res low-5 Å
Luzzati sigma a0.34 Å0.28 Å
Refinement stepCycle: LAST / Resolution: 2→40.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7356 0 210 389 7955
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d1.4
X-RAY DIFFRACTIONc_angle_d1.4
X-RAY DIFFRACTIONc_dihedral_angle_d21.8
X-RAY DIFFRACTIONc_improper_angle_d1.35
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.014
RfactorNum. reflection% reflection
Rfree0.346 618 -
Rwork0.309 --
obs-12004 97 %

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