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- PDB-8f59: LSD1-CoREST in complex with AW2 and SNAG peptide -

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Basic information

Entry
Database: PDB / ID: 8f59
TitleLSD1-CoREST in complex with AW2 and SNAG peptide
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
  • Zinc finger protein SNAI1
KeywordsOXIDOREDUCTASE / Epigenetics / Histone demethylase / Drug resistance / Covalent inhibitor
Function / homology
Function and homology information


negative regulation of cell differentiation involved in embryonic placenta development / cartilage morphogenesis / left/right pattern formation / negative regulation of vitamin D biosynthetic process / Regulation of CDH11 gene transcription / trophoblast giant cell differentiation / epithelial cell migration / epithelial to mesenchymal transition involved in endocardial cushion formation / heterochromatin organization / positive regulation of megakaryocyte differentiation ...negative regulation of cell differentiation involved in embryonic placenta development / cartilage morphogenesis / left/right pattern formation / negative regulation of vitamin D biosynthetic process / Regulation of CDH11 gene transcription / trophoblast giant cell differentiation / epithelial cell migration / epithelial to mesenchymal transition involved in endocardial cushion formation / heterochromatin organization / positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / Epithelial-Mesenchymal Transition (EMT) during gastrulation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / demethylase activity / FAD-dependent H3K4me/H3K4me3 demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / muscle cell development / neuron maturation / positive regulation of neural precursor cell proliferation / MRF binding / regulation of androgen receptor signaling pathway / aortic valve morphogenesis / DNA repair complex / negative regulation of DNA binding / regulation of bicellular tight junction assembly / hair follicle morphogenesis / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of neuroblast proliferation / DNA repair-dependent chromatin remodeling / roof of mouth development / positive regulation of stem cell proliferation / E-box binding / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / mesoderm formation / histone deacetylase complex / histone demethylase activity / positive regulation of cell size / epithelial to mesenchymal transition / canonical Wnt signaling pathway / pericentric heterochromatin / 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 / Notch signaling pathway / transcription repressor complex / negative regulation of protein binding / : / erythrocyte differentiation / positive regulation of protein ubiquitination / Regulation of PTEN gene transcription / epigenetic regulation of gene expression / RNA polymerase II transcription regulatory region sequence-specific DNA binding / promoter-specific chromatin binding / HDACs deacetylate histones / negative regulation of DNA-binding transcription factor activity / cellular response to gamma radiation / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / cerebral cortex development / positive regulation of neuron projection development / kinase binding / fibrillar center / DNA-binding transcription repressor activity, RNA polymerase II-specific / transcription corepressor activity / osteoblast differentiation / cellular response to UV / sequence-specific double-stranded DNA binding / p53 binding / flavin adenine dinucleotide binding / chromatin organization / positive regulation of cold-induced thermogenesis / regulation of protein localization / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / transcription regulator complex / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression / Potential therapeutics for SARS / transcription coactivator activity / chromosome, telomeric region / oxidoreductase activity / positive regulation of cell migration / RNA polymerase II cis-regulatory region sequence-specific DNA binding / negative regulation of gene expression / intracellular membrane-bounded organelle / negative regulation of DNA-templated transcription / chromatin binding / regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / enzyme binding
Similarity search - Function
: / C2H2-type zinc finger / : / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 ...: / C2H2-type zinc finger / : / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / SANT domain profile. / Amine oxidase / Flavin containing amine oxidoreductase / SANT domain / Myb-like DNA-binding domain / SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains / Zinc finger, C2H2 type / SANT/Myb domain / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
: / Lysine-specific histone demethylase 1A / Zinc finger protein SNAI1 / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsCaroli, J. / Mattevi, A.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Association for Cancer ResearchIG19808 Italy
CitationJournal: to be published
Title: Distal drug resistance mutations promote covalent inhibitor-adduct Grob fragmentation in LSD1
Authors: Caroli, J. / Mattevi, A.
History
DepositionNov 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lysine-specific histone demethylase 1A
B: REST corepressor 1
C: Zinc finger protein SNAI1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,6104
Polymers112,6143
Non-polymers9961
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6290 Å2
ΔGint-44 kcal/mol
Surface area37680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.206, 179.201, 236.155
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: 95051.633 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 / Protein CoREST


Mass: 16459.742 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: Protein/peptide Zinc finger protein SNAI1 / Protein snail homolog 1 / Protein sna


Mass: 1102.352 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: O95863
#4: Chemical ChemComp-XB6 / [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2R,3S,4S)-5-{5-[3-([1,1'-biphenyl]-4-yl)propanoyl]-7,8-dimethyl-2,4-dioxo-1,3,4,5-tetrahydrobenzo[g]pteridin-10(2H)-yl}-2,3,4-trihydroxypentyl dihydrogen diphosphate (non-preferred name)


Mass: 995.821 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H47N9O16P2 / 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: 5.65 Å3/Da / Density % sol: 78.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.2 Na/K Tartrate, 100 mM ADA pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.9654 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Sep 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9654 Å / Relative weight: 1
ReflectionResolution: 2.8→48.73 Å / Num. obs: 62710 / % possible obs: 99.7 % / Redundancy: 4.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.043 / Rrim(I) all: 0.096 / Χ2: 0.99 / Net I/σ(I): 10.1 / Num. measured all: 277195
Reflection shellResolution: 2.8→2.87 Å / % possible obs: 99.8 % / Redundancy: 4.3 % / Rmerge(I) obs: 1.535 / Num. measured all: 19524 / Num. unique obs: 4567 / CC1/2: 0.309 / Rpim(I) all: 0.828 / Rrim(I) all: 1.754 / Χ2: 0.99 / Net I/σ(I) obs: 1.1

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.18.2refinement
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2v1d

2v1d


Resolution: 2.8→48.73 Å / SU ML: 0.51 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2344 1233 1.97 %
Rwork0.2206 --
obs0.2209 62630 99.48 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→48.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6328 0 69 0 6397
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0136534
X-RAY DIFFRACTIONf_angle_d1.6728863
X-RAY DIFFRACTIONf_dihedral_angle_d15.686925
X-RAY DIFFRACTIONf_chiral_restr0.084990
X-RAY DIFFRACTIONf_plane_restr0.0121145
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.910.45821410.45746705X-RAY DIFFRACTION99
2.91-3.040.44451360.38216710X-RAY DIFFRACTION99
3.04-3.210.38511360.33356805X-RAY DIFFRACTION100
3.21-3.410.29911360.28486797X-RAY DIFFRACTION100
3.41-3.670.32731130.26226839X-RAY DIFFRACTION100
3.67-4.040.24981290.22286816X-RAY DIFFRACTION100
4.04-4.620.25951370.19856794X-RAY DIFFRACTION99
4.62-5.820.19331460.2016892X-RAY DIFFRACTION100
5.82-48.730.17211590.16897039X-RAY DIFFRACTION99

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