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- PDB-4k9w: Complex of human CYP3A4 with a desoxyritonavir analog -

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Basic information

Entry
Database: PDB / ID: 4k9w
TitleComplex of human CYP3A4 with a desoxyritonavir analog
ComponentsCytochrome P450 3A4
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / cytochrome P450 3A4 / alpha-beta protein / cytochrome P450 fold / 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 / 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 / unspecific monooxygenase / long-chain fatty acid biosynthetic process / Prednisone ADME / Aspirin ADME / steroid metabolic process / androgen metabolic process / xenobiotic catabolic process / cholesterol metabolic process / steroid binding / xenobiotic metabolic process / lipid metabolic process / monooxygenase activity / 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 ...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-7AW / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.399 Å
AuthorsSevrioukova, I.F. / Poulos, T.L.
CitationJournal: Biochemistry / Year: 2013
Title: Dissecting Cytochrome P450 3A4-Ligand Interactions Using Ritonavir Analogues.
Authors: Sevrioukova, I.F. / Poulos, T.L.
History
DepositionApr 21, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 26, 2013Group: Database references
Revision 1.2Jul 17, 2013Group: Database references
Revision 1.3Oct 29, 2014Group: Structure summary
Revision 1.4Oct 25, 2017Group: Author supporting evidence / Category: pdbx_struct_assembly_auth_evidence
Revision 1.5Sep 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_asym_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_label_asym_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

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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
D: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)228,12512
Polymers223,0314
Non-polymers5,0948
Water39622
1
A: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,0313
Polymers55,7581
Non-polymers1,2732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,0313
Polymers55,7581
Non-polymers1,2732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,0313
Polymers55,7581
Non-polymers1,2732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,0313
Polymers55,7581
Non-polymers1,2732
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)94.020, 94.020, 199.412
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31
DetailsMonomeric assembly confirmed by gel filtration (Reference: Sevrioukova I.F. and Poulos T.L., PNAS 2010, 107, 18422-18427)

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Components

#1: Protein
Cytochrome P450 3A4 / 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.: 4 / Mutation: 3-22 deletion
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Strain: human / Gene: CYP3A3, CYP3A4 / 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


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-7AW / N~2~-(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)-N-[(2R,5S)-1-phenyl-5-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}octan-2-yl]-L-valinamide


Mass: 656.902 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C33H48N6O4S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / 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: 2.28 Å3/Da / Density % sol: 46.09 %
Crystal growTemperature: 298 K / Method: microbatch uinder oil / pH: 5.9
Details: PEG 3350, sodium malonate, pH 5.9, microbatch uinder oil, temperature 298K

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 15, 2012 / Details: mirrors
RadiationMonochromator: Yale mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.65
11K, H, -L20.35
ReflectionResolution: 2.399→51.5 Å / Num. all: 77051 / Num. obs: 73892 / % possible obs: 95.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.6 % / Rmerge(I) obs: 0.102 / Net I/σ(I): 8.1
Reflection shellResolution: 2.399→2.53 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.481 / Mean I/σ(I) obs: 2.3 / % possible all: 91

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NXU

3nxu


Resolution: 2.399→47.01 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.95 / SU B: 13.651 / SU ML: 0.137 / Cross valid method: THROUGHOUT / ESU R: 0.108 / ESU R Free: 0.048 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.19815 3687 5 %RANDOM
Rwork0.16387 ---
obs0.16561 70173 95.72 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 60.429 Å2
Baniso -1Baniso -2Baniso -3
1--1.92 Å20 Å20 Å2
2---1.92 Å20 Å2
3---3.84 Å2
Refinement stepCycle: LAST / Resolution: 2.399→47.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14741 0 352 22 15115
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0215492
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8362.01621010
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5551821
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.61323.863642
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.041152759
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.331588
X-RAY DIFFRACTIONr_chiral_restr0.0870.22321
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02111548
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: 2.399→2.461 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.302 236 -
Rwork0.197 4803 -
obs--88.81 %
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)
11.59850.04140.17822.0434-0.1811.2857-0.03080.1319-0.073-0.1866-0.00960.14620.0864-0.10030.04050.09960.01470.01340.0898-0.03440.036241.4061-26.654321.1085
20.95820.52510.27592.4312-0.4110.85470.10060.03080.02830.1415-0.0843-0.03090.05110.0785-0.01630.08510.07320.02510.11180.04080.02277.0239-48.658630.1542
31.63280.01110.02692.15050.27921.00840.1431-0.1094-0.06150.0459-0.0306-0.11290.04540.0759-0.11250.1295-0.046-0.07690.07460.03010.057567.5096-65.3194-17.0011
41.3486-0.69980.07932.3147-0.5191.0493-0.1645-0.07570.14370.3776-0.039-0.1406-0.1629-0.04570.20350.2421-0.0785-0.10010.0958-0.00090.073431.6159-86.7286-9.2419
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A29 - 496
2X-RAY DIFFRACTION1A601 - 602
3X-RAY DIFFRACTION2B29 - 496
4X-RAY DIFFRACTION2B601 - 602
5X-RAY DIFFRACTION3C29 - 496
6X-RAY DIFFRACTION3C601 - 602
7X-RAY DIFFRACTION4D29 - 496
8X-RAY DIFFRACTION4D601 - 602

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