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- PDB-6dwn: Structure of Human Cytochrome P450 1A1 with Erlotinib -

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Basic information

Entry
Database: PDB / ID: 6dwn
TitleStructure of Human Cytochrome P450 1A1 with Erlotinib
ComponentsCytochrome P450 1A1CYP1A1
KeywordsOXIDOREDUCTASE / ligand
Function / homology
Function and homology information


arachidonic acid monooxygenase activity / ethylene metabolic process / flavonoid 3'-monooxygenase activity / insecticide metabolic process / dibenzo-p-dioxin catabolic process / long-chain fatty acid omega-hydroxylase activity / oxidoreductase activity, acting on diphenols and related substances as donors / long-chain fatty acid omega-1 hydroxylase activity / 9-cis-retinoic acid biosynthetic process / hydroperoxy icosatetraenoate dehydratase ...arachidonic acid monooxygenase activity / ethylene metabolic process / flavonoid 3'-monooxygenase activity / insecticide metabolic process / dibenzo-p-dioxin catabolic process / long-chain fatty acid omega-hydroxylase activity / oxidoreductase activity, acting on diphenols and related substances as donors / long-chain fatty acid omega-1 hydroxylase activity / 9-cis-retinoic acid biosynthetic process / hydroperoxy icosatetraenoate dehydratase / hydroperoxy icosatetraenoate dehydratase activity / Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) / omega-hydroxylase P450 pathway / coumarin metabolic process / response to 3-methylcholanthrene / maternal process involved in parturition / porphyrin-containing compound metabolic process / flavonoid metabolic process / response to iron(III) ion / long-chain fatty acid metabolic process / epoxygenase P450 pathway / Biosynthesis of protectins / tissue remodeling / response to nematode / vitamin D 24-hydroxylase activity / estrogen 16-alpha-hydroxylase activity / estrogen 2-hydroxylase activity / lipid hydroxylation / demethylase activity / Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) / vitamin D metabolic process / steroid biosynthetic process / hepatocyte differentiation / Xenobiotics / amine metabolic process / response to arsenic-containing substance / camera-type eye development / digestive tract development / response to vitamin A / hydrogen peroxide biosynthetic process / long-chain fatty acid biosynthetic process / response to herbicide / estrogen metabolic process / retinol metabolic process / unspecific monooxygenase / response to food / aromatase activity / nitric oxide metabolic process / steroid metabolic process / cellular response to organic cyclic compound / response to immobilization stress / response to hyperoxia / positive regulation of G1/S transition of mitotic cell cycle / cellular response to copper ion / Hsp70 protein binding / xenobiotic metabolic process / fatty acid metabolic process / monooxygenase activity / Hsp90 protein binding / PPARA activates gene expression / oxygen binding / response to lipopolysaccharide / mitochondrial inner membrane / oxidoreductase activity / response to hypoxia / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / enzyme binding
Similarity search - Function
Cytochrome P450, E-class, group I, CYP1 / Cytochrome P450, E-class, group I / 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-AQ4 / PROTOPORPHYRIN IX CONTAINING FE / Cytochrome P450 1A1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsBart, A.G. / Scott, E.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM076343 United States
CitationJournal: J. Biol. Chem. / Year: 2018
Title: Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands.
Authors: Bart, A.G. / Scott, E.E.
History
DepositionJun 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 3, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 10, 2018Group: Data collection / Database references / Structure summary
Category: citation / citation_author / entity
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _entity.formula_weight
Revision 1.2Dec 26, 2018Group: Data collection / Database references / Structure summary
Category: citation / entity
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _entity.formula_weight
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 11, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 1A1
B: Cytochrome P450 1A1
C: Cytochrome P450 1A1
D: Cytochrome P450 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)229,04614
Polymers223,7774
Non-polymers5,26910
Water724
1
A: Cytochrome P450 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5694
Polymers55,9441
Non-polymers1,6253
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cytochrome P450 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,5694
Polymers55,9441
Non-polymers1,6253
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Cytochrome P450 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9543
Polymers55,9441
Non-polymers1,0102
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Cytochrome P450 1A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,9543
Polymers55,9441
Non-polymers1,0102
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)64.855, 195.078, 238.013
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31
41

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LYSLYSTYRTYR(chain 'A' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))AA38 - 20711 - 180
12VALVALCYSCYS(chain 'A' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))AA218 - 289191 - 262
13SERSERSERSER(chain 'A' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))AA303 - 512276 - 485
14HEMHEMHEMHEM(chain 'A' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))AE601
25LYSLYSTYRTYR(chain 'B' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))BB38 - 20711 - 180
26VALVALCYSCYS(chain 'B' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))BB218 - 289191 - 262
27SERSERSERSER(chain 'B' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))BB303 - 512276 - 485
28HEMHEMHEMHEM(chain 'B' and (resid 38 through 207 or resid 218 through 289 or resid 303 through 601))BH601
39LYSLYSTYRTYR(chain 'C' and (resid 38 through 207 or resid 218 through 601))CC38 - 20711 - 180
310VALVALCYSCYS(chain 'C' and (resid 38 through 207 or resid 218 through 601))CC218 - 289191 - 262
311SERSERSERSER(chain 'C' and (resid 38 through 207 or resid 218 through 601))CC303 - 512276 - 485
312HEMHEMHEMHEM(chain 'C' and (resid 38 through 207 or resid 218 through 601))CK601
413LYSLYSTYRTYR(chain 'D' and (resid 38 through 289 or resid 303 through 601))DD38 - 20711 - 180
414VALVALCYSCYS(chain 'D' and (resid 38 through 289 or resid 303 through 601))DD218 - 289191 - 262
415SERSERSERSER(chain 'D' and (resid 38 through 289 or resid 303 through 601))DD303 - 512276 - 485
416HEMHEMHEMHEM(chain 'D' and (resid 38 through 289 or resid 303 through 601))DM601

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Components

#1: Protein
Cytochrome P450 1A1 / CYP1A1 / CYPIA1 / Cytochrome P450 form 6 / Cytochrome P450-C / Cytochrome P450-P1


Mass: 55944.156 Da / Num. of mol.: 4 / Fragment: UNP residues 35-512
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP1A1 / Production host: Escherichia coli (E. coli) / References: UniProt: P04798, unspecific monooxygenase
#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-AQ4 / [6,7-BIS(2-METHOXY-ETHOXY)QUINAZOLINE-4-YL]-(3-ETHYNYLPHENYL)AMINE / ERLOTINIB / Erlotinib


Mass: 393.436 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H23N3O4 / Comment: medication*YM
#4: Chemical ChemComp-CPS / 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE / CHAPS / CHAPS detergent


Mass: 614.877 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H58N2O7S / Comment: detergent*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 3.52 Å3/Da / Density % sol: 65.01 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 0.2 M potassium phosphate dibasic, 20% PEG3350, 10% glycerol, 0.5% n-dodecyl-N,N-dimethylamine-N-oxide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 6, 2018
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.99→39.02 Å / Num. obs: 61715 / % possible obs: 99.6 % / Redundancy: 6.6 % / Biso Wilson estimate: 81.06 Å2 / Rpim(I) all: 0.053 / Net I/σ(I): 9.6
Reflection shellResolution: 2.99→3.07 Å / Redundancy: 5.7 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 4346 / Rpim(I) all: 0.755 / % possible all: 96.1

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
XDSdata reduction
Aimless0.6.3data scaling
PHASER2.6.0phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4I8V

4i8v


Resolution: 3→38.98 Å / SU ML: 0.4038 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.1482 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.261 1997 3.26 %
Rwork0.241 59264 -
obs0.2417 61261 99.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 98.19 Å2
Refinement stepCycle: LAST / Resolution: 3→38.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15024 0 159 4 15187
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003815599
X-RAY DIFFRACTIONf_angle_d0.588921203
X-RAY DIFFRACTIONf_chiral_restr0.04222291
X-RAY DIFFRACTIONf_plane_restr0.00332685
X-RAY DIFFRACTIONf_dihedral_angle_d11.33859186
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.070.39221280.40313810X-RAY DIFFRACTION90.36
3.07-3.150.3921400.34544134X-RAY DIFFRACTION98.82
3.15-3.250.3161430.31854255X-RAY DIFFRACTION99.8
3.25-3.350.31191410.32114175X-RAY DIFFRACTION99.84
3.35-3.470.32541390.3184204X-RAY DIFFRACTION99.72
3.47-3.610.29631450.34255X-RAY DIFFRACTION99.86
3.61-3.770.29951400.2834178X-RAY DIFFRACTION99.54
3.77-3.970.2551440.25094243X-RAY DIFFRACTION99.75
3.97-4.220.25631420.24254231X-RAY DIFFRACTION99.95
4.22-4.550.22251450.21964274X-RAY DIFFRACTION99.82
4.55-50.22431450.21534314X-RAY DIFFRACTION99.84
5-5.730.25221440.21414289X-RAY DIFFRACTION100
5.73-7.210.24611480.23224374X-RAY DIFFRACTION99.85
7.21-38.980.23491530.1794528X-RAY DIFFRACTION99.49

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