[English] 日本語
Yorodumi
- PDB-5tfu: Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 5tfu
TitleStructure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex
ComponentsCytochrome P450 2D6CYP2D6
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / CYP2D6 / P450 2D6 / CYTOCHROME P450 / MONOOXYGENASE / BACE1 / OXIDOREDUCTASE-OXIDOREDUCTASE inhibitor complex
Function / homology
Function and homology information


negative regulation of cellular organofluorine metabolic process / Miscellaneous substrates / negative regulation of binding / 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 / arachidonic acid metabolic process / alkaloid catabolic process ...negative regulation of cellular organofluorine metabolic process / Miscellaneous substrates / negative regulation of binding / 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 / arachidonic acid metabolic process / alkaloid catabolic process / anandamide 8,9 epoxidase activity / anandamide 11,12 epoxidase activity / anandamide 14,15 epoxidase activity / alkaloid metabolic process / : / Biosynthesis of maresin-like SPMs / monoterpenoid metabolic process / Xenobiotics / oxidative demethylation / 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 / estrogen metabolic process / retinol 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-P6M / Cytochrome P450 2D6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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)219,28917
Polymers214,9224
Non-polymers4,36713
Water2,234124
1
A: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8715
Polymers53,7311
Non-polymers1,1414
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8064
Polymers53,7311
Non-polymers1,0753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8064
Polymers53,7311
Non-polymers1,0753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Cytochrome P450 2D6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,8064
Polymers53,7311
Non-polymers1,0753
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.105, 191.756, 246.838
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

-
Components

#1: Protein
Cytochrome P450 2D6 / CYP2D6 / 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 / Heme B


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-P6M / (4S,6R)-4-[2,4-difluoro-5-({[1-(trifluoromethyl)cyclopropyl]amino}methyl)phenyl]-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-2-amine


Mass: 393.418 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H20F5N3S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 124 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 3.14 Å3/Da / Density % sol: 60.88 %
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.

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 11, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.75→39.07 Å / Num. obs: 71309 / % possible obs: 99.2 % / Redundancy: 4.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.084 / Net I/σ(I): 12.5
Reflection shellResolution: 2.75→2.81 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.562 / Mean I/σ(I) obs: 3.1 / CC1/2: 0.916 / % possible all: 96.7

-
Processing

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

4xry


Resolution: 2.75→39.07 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.47
RfactorNum. reflection% reflectionSelection details
Rfree0.2497 3521 4.95 %RANDOM
Rwork0.2115 ---
obs0.2134 71085 98.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.75→39.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14292 0 281 124 14697
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00215005
X-RAY DIFFRACTIONf_angle_d0.57420457
X-RAY DIFFRACTIONf_dihedral_angle_d11.5255545
X-RAY DIFFRACTIONf_chiral_restr0.0212215
X-RAY DIFFRACTIONf_plane_restr0.0032704
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7483-2.79560.29771730.27113172X-RAY DIFFRACTION96
2.7956-2.84650.29711850.25853395X-RAY DIFFRACTION100
2.8465-2.90120.34881710.24543319X-RAY DIFFRACTION100
2.9012-2.96040.2881740.24373349X-RAY DIFFRACTION100
2.9604-3.02470.32681780.25513385X-RAY DIFFRACTION99
3.0247-3.09510.31341630.25453275X-RAY DIFFRACTION98
3.0951-3.17240.29891740.24793417X-RAY DIFFRACTION99
3.1724-3.25820.30571750.23113306X-RAY DIFFRACTION100
3.2582-3.3540.2521900.22663400X-RAY DIFFRACTION100
3.354-3.46220.27151670.22613339X-RAY DIFFRACTION100
3.4622-3.58590.30031890.22073419X-RAY DIFFRACTION100
3.5859-3.72930.26121880.22813323X-RAY DIFFRACTION99
3.7293-3.89890.26751710.20563340X-RAY DIFFRACTION98
3.8989-4.10430.20331870.19553404X-RAY DIFFRACTION99
4.1043-4.36110.19461780.1863417X-RAY DIFFRACTION100
4.3611-4.69730.23421750.17733411X-RAY DIFFRACTION100
4.6973-5.1690.2121780.18543411X-RAY DIFFRACTION98
5.169-5.91480.24351630.20243436X-RAY DIFFRACTION99
5.9148-7.44360.23171590.21163486X-RAY DIFFRACTION98
7.4436-39.07490.20251830.18663560X-RAY DIFFRACTION96

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more