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- PDB-5tft: Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 5tft
TitleStructure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex
ComponentsCytochrome P450 2D6
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / CYP2D6 / P450 2D6 / CYTOCHROME P450 / MONOOXYGENASE / BACE1 / OXIDOREDUCTASE-OXIDOREDUCTASE inhibitor complex
Function / homology
Function and homology information


negative regulation of binding / negative regulation of organofluorine metabolic process / Miscellaneous substrates / isoquinoline alkaloid metabolic process / Fatty acids / coumarin metabolic process / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor / CYP2E1 reactions / arachidonate metabolic process / anandamide 8,9 epoxidase activity ...negative regulation of binding / negative regulation of organofluorine metabolic process / Miscellaneous substrates / isoquinoline alkaloid metabolic process / Fatty acids / coumarin metabolic process / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen into the other donor / CYP2E1 reactions / arachidonate metabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid catabolic process / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / alkaloid metabolic process / oxidative demethylation / Xenobiotics / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen / long-chain fatty acid biosynthetic process / retinol metabolic process / estrogen metabolic process / Aspirin ADME / steroid metabolic process / xenobiotic catabolic process / cholesterol metabolic process / xenobiotic metabolic process / monooxygenase activity / oxidoreductase activity / iron ion binding / intracellular membrane-bounded organelle / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum / mitochondrion / cytoplasm
Similarity search - Function
Cytochrome P450, E-class, group I, CYP2D-like / : / 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 ...Cytochrome P450, E-class, group I, CYP2D-like / : / 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-P6U / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.71 Å
AuthorsHsu, M.H. / Johnson, E.F.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM031001 United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.
Authors: Butler, C.R. / Ogilvie, K. / Martinez-Alsina, L. / Barreiro, G. / Beck, E.M. / Nolan, C.E. / Atchison, K. / Benvenuti, E. / Buzon, L. / Doran, S. / Gonzales, C. / Helal, C.J. / Hou, X. / ...Authors: Butler, C.R. / Ogilvie, K. / Martinez-Alsina, L. / Barreiro, G. / Beck, E.M. / Nolan, C.E. / Atchison, K. / Benvenuti, E. / Buzon, L. / Doran, S. / Gonzales, C. / Helal, C.J. / Hou, X. / Hsu, M.H. / Johnson, E.F. / Lapham, K. / Lanyon, L. / Parris, K. / O'Neill, B.T. / Riddell, D. / Robshaw, A. / Vajdos, F. / Brodney, M.A.
History
DepositionSep 26, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2017Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 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
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_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.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr2_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_asym_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.ptnr1_symmetry / _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_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cytochrome P450 2D6
B: Cytochrome P450 2D6
C: Cytochrome P450 2D6
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)219,23317
Polymers214,9224
Non-polymers4,31113
Water75742
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8575
Polymers53,7311
Non-polymers1,1274
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7924
Polymers53,7311
Non-polymers1,0613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7924
Polymers53,7311
Non-polymers1,0613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7924
Polymers53,7311
Non-polymers1,0613
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.474, 192.563, 247.901
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Cytochrome P450 2D6 / CYPIID6 / Cholesterol 25-hydroxylase / Cytochrome P450-DB1 / Debrisoquine 4-hydroxylase


Mass: 53730.566 Da / Num. of mol.: 4 / Fragment: UNP residues 34-497
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP2D6, CYP2DL1 / Plasmid: PCWORI / Production host: Escherichia coli DH5[alpha] (bacteria) / Strain (production host): DH5ALPHA / References: UniProt: P10635, unspecific monooxygenase
#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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-P6U / (4S)-4-[2,4-difluoro-5-({[1-(trifluoromethyl)cyclopropyl]amino}methyl)phenyl]-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine


Mass: 379.391 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H18F5N3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 3.19 Å3/Da / Density % sol: 61.46 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. BETA- ...Details: PEG3350, SODIUM ACETATE, SODIUM CACODYLATE, POTASSIUM PHOSPHATE, SODIUM CHLORIDE, ZINC CHLORIDE, GLYCEROL, BETA-MERCAPTOETHANOL, THIORIDAZINE, HEGA-10, FACIAL AMPHIPHILE 231_CHOL. BETA-SECRETASE INHIBITOR WAS ADDED TO THE MOTHER LIQUOR AFTER CRYSTALLIZATION OF THE P450 2D6 THIORDIDAZINE TERNARY COMPLEX.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9252 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9252 Å / Relative weight: 1
ReflectionResolution: 2.71→39.24 Å / Num. obs: 75700 / % possible obs: 99.6 % / Redundancy: 6 % / CC1/2: 0.987 / Rmerge(I) obs: 0.094 / Net I/σ(I): 15.3
Reflection shellResolution: 2.71→2.77 Å / Redundancy: 5.9 % / Rmerge(I) obs: 0.585 / Mean I/σ(I) obs: 3 / CC1/2: 0.878 / % possible all: 97

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4XRY

4xry


Resolution: 2.71→39.238 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.07
RfactorNum. reflection% reflectionSelection details
Rfree0.2452 3760 4.98 %Random selection
Rwork0.2111 ---
obs0.2128 75508 99.37 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.71→39.238 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14460 0 277 42 14779
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00315176
X-RAY DIFFRACTIONf_angle_d0.61520692
X-RAY DIFFRACTIONf_dihedral_angle_d11.7965604
X-RAY DIFFRACTIONf_chiral_restr0.0222237
X-RAY DIFFRACTIONf_plane_restr0.0032739
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7102-2.74450.30521430.28682529X-RAY DIFFRACTION95
2.7445-2.78060.31791460.27162572X-RAY DIFFRACTION100
2.7806-2.81870.29411410.25452599X-RAY DIFFRACTION99
2.8187-2.8590.31191500.25262657X-RAY DIFFRACTION100
2.859-2.90160.29861280.25842599X-RAY DIFFRACTION99
2.9016-2.9470.30821270.25182603X-RAY DIFFRACTION99
2.947-2.99520.36331440.25132654X-RAY DIFFRACTION100
2.9952-3.04690.33431390.25232636X-RAY DIFFRACTION100
3.0469-3.10230.30861360.23772620X-RAY DIFFRACTION100
3.1023-3.16190.28411230.24582673X-RAY DIFFRACTION100
3.1619-3.22640.30761420.24412644X-RAY DIFFRACTION100
3.2264-3.29650.24441450.23622621X-RAY DIFFRACTION100
3.2965-3.37320.27541530.23522655X-RAY DIFFRACTION100
3.3732-3.45750.24111290.2182616X-RAY DIFFRACTION100
3.4575-3.55090.28461430.21682663X-RAY DIFFRACTION100
3.5509-3.65530.2571400.22982654X-RAY DIFFRACTION100
3.6553-3.77320.26331640.21322617X-RAY DIFFRACTION100
3.7732-3.9080.24681290.20262668X-RAY DIFFRACTION99
3.908-4.06430.21671380.19382686X-RAY DIFFRACTION100
4.0643-4.2490.19331360.18922663X-RAY DIFFRACTION100
4.249-4.47280.19691570.17782692X-RAY DIFFRACTION100
4.4728-4.75260.19841360.16582686X-RAY DIFFRACTION100
4.7526-5.11880.21661390.18312694X-RAY DIFFRACTION100
5.1188-5.63250.22841350.20272718X-RAY DIFFRACTION100
5.6325-6.44450.24111270.21692726X-RAY DIFFRACTION98
6.4445-8.10760.22121240.19292779X-RAY DIFFRACTION100
8.1076-39.24190.18981460.18442824X-RAY DIFFRACTION97

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