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- PDB-2xaf: Crystal structure of LSD1-CoREST in complex with para-bromo-(+)-c... -

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Basic information

Entry
Database: PDB / ID: 2xaf
TitleCrystal structure of LSD1-CoREST in complex with para-bromo-(+)-cis-2- phenylcyclopropyl-1-amine
Components
  • LYSINE-SPECIFIC HISTONE DEMETHYLASE 1
  • REST COREPRESSOR 1
KeywordsTRANSCRIPTION / AMINE OXIDASE / CHROMATIN REGULATOR / HISTONE INHIBITOR BINDING / METHYLATION / NUCLEOSOME CORE / OXIDOREDUCTASE / OXIDOREDUCTASE-REPRESSOR COMPLEX / CHROMATIN REMODELLING
Function / homology
Function and homology information


positive regulation of megakaryocyte differentiation / guanine metabolic process / : / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development ...positive regulation of megakaryocyte differentiation / guanine metabolic process / : / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development / neuron maturation / positive regulation of neural precursor cell proliferation / regulation of androgen receptor signaling pathway / MRF binding / DNA repair complex / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / DNA repair-dependent chromatin remodeling / positive regulation of neuroblast proliferation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of stem cell proliferation / negative regulation of DNA binding / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase complex / positive regulation of cell size / histone demethylase activity / positive regulation of epithelial to mesenchymal transition / response to fungicide / cellular response to cAMP / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / transcription repressor complex / erythrocyte differentiation / nuclear receptor coactivator activity / positive regulation of protein ubiquitination / negative regulation of protein binding / Regulation of PTEN gene transcription / HDACs deacetylate histones / promoter-specific chromatin binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / negative regulation of DNA-binding transcription factor activity / HDMs demethylate histones / cellular response to gamma radiation / cerebral cortex development / positive regulation of neuron projection development / transcription corepressor activity / cellular response to UV / p53 binding / flavin adenine dinucleotide binding / positive regulation of cold-induced thermogenesis / regulation of protein localization / chromatin organization / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription regulator complex / Potential therapeutics for SARS / chromosome, telomeric region / transcription coactivator activity / oxidoreductase activity / chromatin remodeling / negative regulation of gene expression / negative regulation of DNA-templated transcription / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / SANT domain profile. / SANT domain / Amine oxidase / Flavin containing amine oxidoreductase / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / SANT/Myb domain / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Helix Hairpins / Arc Repressor Mutant, subunit A / Winged helix-like DNA-binding domain superfamily / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / 3-(4-BROMOPHENYL)PROPANAMIDE / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.25 Å
AuthorsBinda, C. / Valente, S. / Romanenghi, M. / Pilotto, S. / Cirilli, R. / Karytinos, A. / Ciossani, G. / Botrugno, O.A. / Forneris, F. / Tardugno, M. ...Binda, C. / Valente, S. / Romanenghi, M. / Pilotto, S. / Cirilli, R. / Karytinos, A. / Ciossani, G. / Botrugno, O.A. / Forneris, F. / Tardugno, M. / Edmondson, D.E. / Minucci, S. / Mattevi, A. / Mai, A.
CitationJournal: J.Am.Chem.Soc. / Year: 2010
Title: Biochemical, Structural, and Biological Evaluation of Tranylcypromine Derivatives as Inhibitors of Histone Demethylases Lsd1 and Lsd2.
Authors: Binda, C. / Valente, S. / Romanenghi, M. / Pilotto, S. / Cirilli, R. / Karytinos, A. / Ciossani, G. / Botrugno, O.A. / Forneris, F. / Tardugno, M. / Edmondson, D.E. / Minucci, S. / Mattevi, A. / Mai, A.
History
DepositionMar 31, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 5, 2010Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2011Group: Database references / Version format compliance
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _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: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1
B: REST COREPRESSOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,1274
Polymers146,1132
Non-polymers1,0142
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7300 Å2
ΔGint-47.1 kcal/mol
Surface area38010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)119.560, 179.480, 235.420
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein LYSINE-SPECIFIC HISTONE DEMETHYLASE 1 / LYSINE-SPECIFIC HISTONE DEMETHYLASE LSD1 / FLAVIN-CONTAINING AMINE OXIDASE DOMAIN-CONTAINING ...LYSINE-SPECIFIC HISTONE DEMETHYLASE LSD1 / FLAVIN-CONTAINING AMINE OXIDASE DOMAIN-CONTAINING PROTEIN 2 / BRAF35-HDAC COMPLEX PROTEIN BHC110


Mass: 93011.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: O60341, Oxidoreductases
#2: Protein REST COREPRESSOR 1 / COREPRESSOR COREST / PROTEIN COREST


Mass: 53101.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q9UKL0
#3: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#4: Chemical ChemComp-TCF / 3-(4-BROMOPHENYL)PROPANAMIDE / PARA-BROMO-CIS-2-PHENYLCYCLOPROPYL-1-AMINE


Mass: 228.086 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H10BrNO
Nonpolymer detailsPARA-BROMO-CIS-2-PHENYLCYCLOPROPYL-1-AMINE IS AN INHIBITOR THAT HAS REACTED COVALENTLY WITH FAD. ...PARA-BROMO-CIS-2-PHENYLCYCLOPROPYL-1-AMINE IS AN INHIBITOR THAT HAS REACTED COVALENTLY WITH FAD. THE COVALENT LINKAGE IS BETWEEN THE N5 ATOM OF FAD AND THE C1B ATOM OF TCF.

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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: 4.32 Å3/Da / Density % sol: 71.5 % / Description: NONE
Crystal growDetails: SODIUM/POTASSIUM TARTRATE, ADA BUFFER PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.98
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 3.2→30 Å / Num. obs: 39882 / % possible obs: 95.1 % / Observed criterion σ(I): 2 / Redundancy: 2.5 % / Biso Wilson estimate: 30 Å2 / Rmerge(I) obs: 0.12

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Processing

Software
NameVersionClassification
REFMAC5.5.0090refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.25→30.51 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.915 / SU B: 15.788 / SU ML: 0.255 / Cross valid method: THROUGHOUT / ESU R: 0.493 / ESU R Free: 0.314 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22853 735 1.9 %RANDOM
Rwork0.20197 ---
obs0.20251 37289 94.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 67.882 Å2
Baniso -1Baniso -2Baniso -3
1-6.5 Å20 Å20 Å2
2---3.85 Å20 Å2
3----2.65 Å2
Refinement stepCycle: LAST / Resolution: 3.25→30.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 64 0 6357
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0226492
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6671.9758809
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8725797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.19624.475295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg22.881151130
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4671542
X-RAY DIFFRACTIONr_chiral_restr0.1120.2987
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214888
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_it0.7491.53984
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.43126437
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.60732508
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9294.52372
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: 3.25→3.333 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.375 50 -
Rwork0.297 2792 -
obs--98.1 %

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