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- PDB-8jf5: Crystal structure of Lysine Specific Demethylase 1 (LSD1) with TAS1440 -

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Basic information

Entry
Database: PDB / ID: 8jf5
TitleCrystal structure of Lysine Specific Demethylase 1 (LSD1) with TAS1440
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1RCOR1
KeywordsFLAVOPROTEIN / Histone demethylase
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 / regulation of DNA methylation-dependent heterochromatin formation / 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 / regulation of DNA methylation-dependent heterochromatin formation / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development / positive regulation of neural precursor cell proliferation / neuron maturation / regulation of androgen receptor signaling pathway / MRF binding / DNA repair complex / DNA repair-dependent chromatin remodeling / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / 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 / 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 / regulation of protein localization / p53 binding / positive regulation of cold-induced thermogenesis / chromatin organization / flavin adenine dinucleotide binding / 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 / negative regulation of gene expression / negative regulation of DNA-templated transcription / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / identical protein binding / nucleus
Similarity search - Function
: / Helical region in REST corepressor / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / SWIRM domain / SWIRM domain / SWIRM domain profile. ...: / Helical region in REST corepressor / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / 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 / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / : / 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
AuthorsFukushima, H. / Machida, T. / Yamashita, S. / Suzuki, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: TAS1440, a histone H3 competitive LSD1 inhibitor, activates both TGF-beta and notch signaling pathways via INSM1 dissociation in neuroendocrine small cell lung cancer
Authors: Machida, T. / Tsukioka, S. / Gong, Y. / Onodera, A. / Nakayama, A. / Hashimoto, N. / Ohkubo, S. / Tanaka, T.
History
DepositionMay 17, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 22, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lysine-specific histone demethylase 1A
B: REST corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,6606
Polymers89,2152
Non-polymers1,4454
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4670 Å2
ΔGint-46 kcal/mol
Surface area35540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.772, 179.115, 235.029
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 1A / BRAF35-HDAC complex protein BHC110 / Flavin-containing amine oxidase domain-containing protein 2 / ...BRAF35-HDAC complex protein BHC110 / Flavin-containing amine oxidase domain-containing protein 2 / [histone H3]-dimethyl-L-lysine(4) FAD-dependent demethylase 1A


Mass: 73709.289 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM1A, AOF2, KDM1, KIAA0601, LSD1 / Production host: Escherichia coli (E. coli)
References: UniProt: O60341, [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase
#2: Protein REST corepressor 1 / RCOR1 / Protein CoREST


Mass: 15505.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RCOR1, KIAA0071, RCOR / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UKL0
#3: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-UEU / 4-[5-[(3~{R})-3-azanylpyrrolidin-1-yl]carbonyl-2-[2-fluoranyl-4-(2-methyl-2-oxidanyl-propyl)phenyl]phenyl]-2-fluoranyl-benzenecarbonitrile


Mass: 475.530 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H27F2N3O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 7.18 Å3/Da / Density % sol: 82.87 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5 / Details: 100mM ADA pH6.5, 1.22M Na/K Tartrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-1A / Wavelength: 1.08 Å
DetectorType: DECTRIS EIGER X 4M / Detector: PIXEL / Date: Oct 30, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.08 Å / Relative weight: 1
ReflectionResolution: 3.2→49.13 Å / Num. obs: 42711 / % possible obs: 100 % / Redundancy: 6.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.11 / Rrim(I) all: 0.119 / Net I/σ(I): 13.3
Reflection shellResolution: 3.2→3.37 Å / Redundancy: 7.2 % / Rmerge(I) obs: 0.877 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 6138 / CC1/2: 0.853 / Rrim(I) all: 0.945 / % possible all: 100

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Processing

SoftwareName: REFMAC / Version: 5.8.0158 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.2→49.13 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.922 / SU B: 15.438 / SU ML: 0.239 / Cross valid method: THROUGHOUT / ESU R: 0.374 / ESU R Free: 0.287 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23025 2145 5 %RANDOM
Rwork0.19266 ---
obs0.19451 40566 99.94 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 90.082 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å2-0 Å2-0 Å2
2--0 Å2-0 Å2
3---0.02 Å2
Refinement stepCycle: 1 / Resolution: 3.2→49.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5856 0 100 0 5956
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0196085
X-RAY DIFFRACTIONr_bond_other_d0.0030.025440
X-RAY DIFFRACTIONr_angle_refined_deg2.3231.9738325
X-RAY DIFFRACTIONr_angle_other_deg1.3312516
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.8895792
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.74224.5240
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.08215873
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3991529
X-RAY DIFFRACTIONr_chiral_restr0.1110.2970
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0216883
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021203
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_it9.4589.4893174
X-RAY DIFFRACTIONr_mcbond_other9.459.4873173
X-RAY DIFFRACTIONr_mcangle_it13.89414.223964
X-RAY DIFFRACTIONr_mcangle_other13.89214.2233965
X-RAY DIFFRACTIONr_scbond_it10.2319.7232910
X-RAY DIFFRACTIONr_scbond_other10.2299.7222911
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other14.94414.3644362
X-RAY DIFFRACTIONr_long_range_B_refined17.4267173
X-RAY DIFFRACTIONr_long_range_B_other17.4257174
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
Rfree0.42 170 -
Rwork0.412 2936 -
obs--100 %

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