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- PDB-5g5j: Crystal structure of human CYP3A4 bound to metformin -

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Basic information

Entry
Database: PDB / ID: 5g5j
TitleCrystal structure of human CYP3A4 bound to metformin
ComponentsCYTOCHROME P450 3A4CYP3A4
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 / 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
PROTOPORPHYRIN IX CONTAINING FE / Metformin / Cytochrome P450 3A4
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsSevrioukova, I.
CitationJournal: Cell Chem Biol / Year: 2017
Title: Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.
Authors: Guo, Z. / Sevrioukova, I.F. / Denisov, I.G. / Zhang, X. / Chiu, T.L. / Thomas, D.G. / Hanse, E.A. / Cuellar, R.A.D. / Grinkova, Y.V. / Langenfeld, V.W. / Swedien, D.S. / Stamschror, J.D. / ...Authors: Guo, Z. / Sevrioukova, I.F. / Denisov, I.G. / Zhang, X. / Chiu, T.L. / Thomas, D.G. / Hanse, E.A. / Cuellar, R.A.D. / Grinkova, Y.V. / Langenfeld, V.W. / Swedien, D.S. / Stamschror, J.D. / Alvarez, J. / Luna, F. / Galvan, A. / Bae, Y.K. / Wulfkuhle, J.D. / Gallagher, R.I. / Petricoin, E.F. / Norris, B. / Flory, C.M. / Schumacher, R.J. / O'Sullivan, M.G. / Cao, Q. / Chu, H. / Lipscomb, J.D. / Atkins, W.M. / Gupta, K. / Kelekar, A. / Blair, I.A. / Capdevila, J.H. / Falck, J.R. / Sligar, S.G. / Poulos, T.L. / Georg, G.I. / Ambrose, E. / Potter, D.A.
History
DepositionMay 25, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 7, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 1, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 10, 2024Group: 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)56,5033
Polymers55,7581
Non-polymers7462
Water46826
1
A: CYTOCHROME P450 3A4
hetero molecules

A: CYTOCHROME P450 3A4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,0076
Polymers111,5162
Non-polymers1,4914
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area3440 Å2
ΔGint-58.4 kcal/mol
Surface area38590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.000, 101.070, 128.370
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-2014-

HOH

21A-2017-

HOH

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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 / 1.14.13.67 / TAUROCHENODEOXYCHOLATE 6-ALPHA-HYDROXYLASE


Mass: 55757.812 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 1-2,23-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PCWORI-CYP3A4 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21
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, unspecific monooxygenase, EC: 1.14.13.67, EC: 1.14.13.97
#2: Chemical ChemComp-MF8 / Metformin / N,N-Dimethylimidodicarbonimidic diamide / Metformin


Mass: 129.164 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H11N5 / Comment: medication*YM
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 26 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsPROTOPORPHYRIN IX CONTAINING FE (HEM): HEME METFORMIN (MF8): N/A
Sequence detailsRESIDUES 3-22 DETETED, ADDITIONAL C-TERMINAL 4-HISTIDINE TAG

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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: 2.27 Å3/Da / Density % sol: 45.86 %
Crystal growpH: 7 / Details: 12% PEG 3350, 0.1M SODIUM ACETATE PH 7.0

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 8, 2012 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→44.31 Å / Num. obs: 15443 / % possible obs: 98.2 % / Observed criterion σ(I): 2 / Redundancy: 4.4 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 10.5
Reflection shellResolution: 2.6→2.72 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.56 / Mean I/σ(I) obs: 2 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
MOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3UA1

3ua1


Resolution: 2.6→37.4 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.914 / SU B: 30.94 / SU ML: 0.303 / Cross valid method: THROUGHOUT / ESU R Free: 0.375 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 24-27, 260-269, 280-286 AND C-TERMINUS ARE DISORDERED THE N- AND C-TERMINI AND THE 260-269 AND 280-286 FRAGMENTS ARE DISORDERED
RfactorNum. reflection% reflectionSelection details
Rfree0.27942 770 5 %RANDOM
Rwork0.20227 ---
obs0.20608 14657 97.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 71.742 Å2
Baniso -1Baniso -2Baniso -3
1-0.03 Å2-0 Å2-0 Å2
2---0.16 Å2-0 Å2
3---0.13 Å2
Refinement stepCycle: LAST / Resolution: 2.6→37.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3639 0 52 26 3717
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193787
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4722.0065136
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8475449
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.02823.885157
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.39315680
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3291520
X-RAY DIFFRACTIONr_chiral_restr0.1020.2566
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212826
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_it3.2335.4471805
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.0268.1582251
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.6065.6051981
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
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: 2.6→2.667 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.353 59 -
Rwork0.257 1095 -
obs--99.31 %
Refinement TLS params.Method: refined / Origin x: 19.1266 Å / Origin y: -23.5143 Å / Origin z: 13.5138 Å
111213212223313233
T0.0296 Å2-0.0242 Å2-0.0045 Å2-0.113 Å20.0337 Å2--0.0298 Å2
L1.3022 °21.0548 °2-0.2788 °2-2.8271 °2-0.4085 °2--0.7458 °2
S0.0663 Å °-0.1976 Å °-0.0455 Å °-0.0873 Å °-0.1199 Å °0.1148 Å °0.1032 Å °-0.0294 Å °0.0536 Å °

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