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- PDB-2xaq: Crystal structure of LSD1-CoREST in complex with a tranylcypromin... -

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Basic information

Entry
Database: PDB / ID: 2xaq
TitleCrystal structure of LSD1-CoREST in complex with a tranylcypromine derivative (MC2584, 13b)
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 / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / cellular response to cAMP / transcription repressor complex / erythrocyte differentiation / nuclear receptor coactivator activity / negative regulation of protein binding / Regulation of PTEN gene transcription / positive regulation of protein ubiquitination / HDACs deacetylate histones / promoter-specific chromatin binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / negative regulation of DNA-binding transcription factor activity / 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 / chromatin organization / regulation of protein localization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / 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-[(PHENYLCARBONYL)AMINO]PHENYL}PROPANOIC ACID / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 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 / Refinement description / 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)147,1684
Polymers146,1132
Non-polymers1,0552
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6720 Å2
ΔGint-46.8 kcal/mol
Surface area37790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.102, 180.346, 235.928
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-M84 / 3-{4-[(PHENYLCARBONYL)AMINO]PHENYL}PROPANOIC ACID


Mass: 269.295 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15NO3
Nonpolymer detailsMC2584 IS AN INHIBITOR THAT HAS REACTED COVALENTLY WITH FAD. THE COVALENT LINKAGE IS BETWEEN THE N5 ...MC2584 IS AN INHIBITOR THAT HAS REACTED COVALENTLY WITH FAD. THE COVALENT LINKAGE IS BETWEEN THE N5 ATOM OF FAD AND THE C1B ATOM OF M84.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.37 Å3/Da / Density % sol: 71.8 % / 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: SLS / Beamline: X06SA / Wavelength: 0.97
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 3.2→30 Å / Num. obs: 42599 / % possible obs: 99.9 % / Observed criterion σ(I): 2 / Redundancy: 5.1 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 9.2

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→99.96 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.906 / SU B: 15.28 / SU ML: 0.26 / Cross valid method: THROUGHOUT / ESU R: 0.489 / ESU R Free: 0.332 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2638 822 1.9 %RANDOM
Rwork0.2428 ---
obs0.24324 41775 99.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 92.591 Å2
Baniso -1Baniso -2Baniso -3
1-11.58 Å20 Å20 Å2
2---16.4 Å20 Å2
3---4.81 Å2
Refinement stepCycle: LAST / Resolution: 3.2→99.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 72 0 6365
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0226501
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.0741.9768821
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.9115797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.0724.475295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg24.81151130
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4361542
X-RAY DIFFRACTIONr_chiral_restr0.1430.2987
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0214898
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_it0.9241.53984
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.73926437
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.10732517
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.734.52384
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: 3.2→3.283 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.449 58 -
Rwork0.433 3052 -
obs--100 %

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