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- PDB-3abt: Crystal Structure of LSD1 in complex with trans-2-pentafluorophen... -

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Basic information

Entry
Database: PDB / ID: 3abt
TitleCrystal Structure of LSD1 in complex with trans-2-pentafluorophenylcyclopropylamine
ComponentsLysine-specific histone demethylase 1
KeywordsOXIDOREDUCTASE / Amine Oxidase / Histone demethylase / Tower domain / H3K4 / Structural Genomics / RIKEN Structural Genomics/Proteomics Initiative / RSGI / Chromatin regulator / Developmental protein / FAD / Nucleus / Phosphoprotein / Repressor / Transcription / Transcription regulation / NPPSFA / National Project on Protein Structural and Functional Analyses
Function / homology
Function and homology information


guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylase activity / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / [histone H3]-dimethyl-L-lysine9 demethylase / histone H4K20 demethylase activity / histone H3K4 demethylase activity / telomeric repeat-containing RNA binding / neuron maturation ...guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylase activity / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / [histone H3]-dimethyl-L-lysine9 demethylase / histone H4K20 demethylase activity / histone H3K4 demethylase activity / telomeric repeat-containing RNA binding / neuron maturation / muscle cell development / Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / MRF binding / regulation of androgen receptor signaling pathway / positive regulation of neural precursor cell proliferation / DNA repair complex / nuclear androgen receptor binding / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of neuroblast proliferation / regulation of double-strand break repair via homologous recombination / positive regulation of stem cell proliferation / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / DNA repair-dependent chromatin remodeling / histone methyltransferase complex / histone demethylase activity / positive regulation of cell size / positive regulation of epithelial to mesenchymal transition / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / response to fungicide / epigenetic regulation of gene expression / cellular response to cAMP / positive regulation of protein ubiquitination / 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 / HDMs demethylate histones / positive regulation of neuron projection development / cellular response to gamma radiation / cerebral cortex development / Negative Regulation of CDH1 Gene Transcription / p53 binding / cellular response to UV / transcription corepressor activity / flavin adenine dinucleotide binding / regulation of protein localization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / transcription regulator complex / Estrogen-dependent gene expression / DNA-binding transcription factor binding / Potential therapeutics for SARS / RNA polymerase II-specific DNA-binding transcription factor binding / transcription coactivator activity / chromosome, telomeric region / oxidoreductase activity / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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
Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / Amine oxidase / Flavin containing amine oxidoreductase / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Homeobox-like domain superfamily ...Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / Amine oxidase / Flavin containing amine oxidoreductase / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-2PF / Lysine-specific histone demethylase 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.2 Å
AuthorsMimasu, S. / Umezawa, N. / Sato, S. / Higuchi, T. / Umehara, T. / Yokoyama, S. / RIKEN Structural Genomics/Proteomics Initiative (RSGI)
CitationJournal: Biochemistry / Year: 2010
Title: Structurally Designed trans-2-Phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1
Authors: Mimasu, S. / Umezawa, N. / Sato, S. / Higuchi, T. / Umehara, T. / Yokoyama, S.
History
DepositionDec 21, 2009Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 7, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 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 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)74,6622
Polymers73,6521
Non-polymers1,0101
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)183.840, 183.840, 109.150
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

#1: Protein Lysine-specific histone demethylase 1 / LSD1 / Flavin-containing amine oxidase domain-containing protein 2 / BRAF35-HDAC complex protein BHC110


Mass: 73652.242 Da / Num. of mol.: 1
Fragment: amine oxidase (flavin containing) domain 2, residues 172-833
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: Kazusa DNA KIAA 0601 / Plasmid: pGEX-6P-Hs / Production host: Escherichia coli (E. coli) / Strain (production host): BL-21 / References: UniProt: O60341
#2: Chemical ChemComp-2PF / [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl]methyl (2R,3S,4S)-2,3,4-trihydroxy-5-[(1R,3R,3aS)-1-hydroxy-10,11-dimethyl-4,6-dioxo-3-(pentafluorophenyl)-2,3,5,6-tetrahydro-1H-benzo[g]pyrrolo[2,1-e]pteridin-8(4H)-yl]pentyl dihydrogen diphosphate


Mass: 1009.677 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H38F5N9O16P2

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 2

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Sample preparation

CrystalDensity Matthews: 3.61 Å3/Da / Density % sol: 65.97 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 3-10% PEG 2000 Monomethyl ether, 0.1M Hepes pH 7.5, 0.2M magnesium chloride, 0.1M cacodylate, 5mM Tranylcypromine-derivative, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

Diffraction
IDMean temperature (K)Crystal-ID
11001
21001
Diffraction source
SourceSiteBeamlineIDWavelength (Å)
SYNCHROTRONSPring-8 BL41XU11
SYNCHROTRONSPring-8 BL26B221
Detector
TypeIDDetectorDate
ADSC QUANTUM 3151CCDApr 15, 2008
MARMOSAIC 225 mm CCD2CCDDec 3, 2008
Radiation
IDMonochromatorProtocolMonochromatic (M) / Laue (L)Scattering typeWavelength-ID
1nativeSINGLE WAVELENGTHMx-ray1
2nativeSINGLE WAVELENGTHMx-ray1
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 18396 / % possible obs: 99 % / Redundancy: 8.7 % / Rsym value: 0.226 / Net I/σ(I): 9.77 / Num. measured all: 177168
Reflection shellResolution: 3.21→3.34 Å / Redundancy: 4.4 % / Rmerge(I) obs: 0.612 / Mean I/σ(I) obs: 2.11 / Num. unique all: 2820 / Rsym value: 0.612 / % possible all: 98.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
CNS1.2refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2DW4

2dw4


Resolution: 3.2→47.73 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 3724656.61 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 2.1 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.272 893 4.9 %RANDOM
Rwork0.231 ---
obs0.231 18396 99.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 16.9251 Å2 / ksol: 0.3 e/Å3
Displacement parametersBiso mean: 58.9 Å2
Baniso -1Baniso -2Baniso -3
1-9.78 Å20 Å20 Å2
2--9.78 Å20 Å2
3----19.57 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.49 Å0.4 Å
Luzzati d res low-5 Å
Luzzati sigma a0.62 Å0.61 Å
Refinement stepCycle: LAST / Resolution: 3.2→47.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5049 0 68 0 5117
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.003
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.7
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it0.571.5
X-RAY DIFFRACTIONc_mcangle_it1.072
X-RAY DIFFRACTIONc_scbond_it0.472
X-RAY DIFFRACTIONc_scangle_it0.862.5
LS refinement shellResolution: 3.2→3.4 Å / Rfactor Rfree error: 0.029 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.361 150 5.1 %
Rwork0.332 2820 -
obs-2820 99.1 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2drgmsoxflu3.paramdrgmsoxflu3.top
X-RAY DIFFRACTION3water_rep.paramwater_rep.param

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