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- PDB-8fdv: LSD1-CoREST in complex N-formyl FAD and SNAG peptide -

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Basic information

Entry
Database: PDB / ID: 8fdv
TitleLSD1-CoREST in complex N-formyl FAD 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 / epithelial cell migration / epithelial to mesenchymal transition involved in endocardial cushion formation / trophoblast giant cell differentiation / positive regulation of megakaryocyte differentiation / guanine metabolic process ...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 / epithelial cell migration / epithelial to mesenchymal transition involved in endocardial cushion formation / trophoblast giant cell differentiation / positive regulation of megakaryocyte differentiation / guanine metabolic process / regulation of DNA methylation-dependent heterochromatin formation / protein demethylation / [histone H3]-N6,N6-dimethyl-L-lysine4 FAD-dependent demethylase / FAD-dependent H3K4me/H3K4me3 demethylase activity / Epithelial-Mesenchymal Transition (EMT) during gastrulation / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / muscle cell development / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage / neuron maturation / positive regulation of neural precursor cell proliferation / regulation of androgen receptor signaling pathway / MRF binding / aortic valve morphogenesis / regulation of bicellular tight junction assembly / DNA repair complex / DNA repair-dependent chromatin remodeling / nuclear androgen receptor binding / hair follicle morphogenesis / 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 / roof of mouth development / positive regulation of stem cell proliferation / E-box binding / negative regulation of DNA binding / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase complex / mesoderm formation / positive regulation of cell size / histone demethylase activity / epithelial to mesenchymal transition / canonical Wnt signaling pathway / pericentric heterochromatin / heterochromatin organization / positive regulation of epithelial to mesenchymal transition / response to fungicide / cellular response to cAMP / Notch signaling pathway / 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 / RNA polymerase II transcription regulatory region sequence-specific DNA 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 / fibrillar center / kinase binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / positive regulation of neuron projection development / osteoblast differentiation / transcription corepressor activity / regulation of protein localization / cellular response to UV / sequence-specific double-stranded DNA binding / p53 binding / chromatin organization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / flavin adenine dinucleotide binding / 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 / oxidoreductase activity / transcription coactivator 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 / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II
Similarity search - Function
C2H2-type zinc finger / : / Helical region in REST corepressor / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / SWIRM domain / SWIRM domain ...C2H2-type zinc finger / : / 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 / 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
Chem-HUF / 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: 2.95 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
DepositionDec 5, 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)113,4294
Polymers112,6143
Non-polymers8161
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6880 Å2
ΔGint-48 kcal/mol
Surface area37750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)119.298, 180.388, 232.884
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: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SNAI1, SNAH / Production host: Escherichia coli (E. coli) / References: UniProt: O95863
#4: Chemical ChemComp-HUF / [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2R,3S,4S)-5-[5-methanoyl-7,8-dimethyl-2,4-bis(oxidanylidene)-1H-benzo[g]pteridin-10-yl]-2,3,4-tris(oxidanyl)pentyl] hydrogen phosphate


Mass: 815.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H35N9O16P2 / 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: 5.56 Å3/Da / Density % sol: 77.89 %
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: 0.96546 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Feb 22, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96546 Å / Relative weight: 1
ReflectionResolution: 2.95→48.92 Å / Num. obs: 52843 / % possible obs: 99.5 % / Redundancy: 4.2 % / CC1/2: 0.996 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.058 / Rrim(I) all: 0.124 / Χ2: 1.01 / Net I/σ(I): 8.2 / Num. measured all: 222491
Reflection shellResolution: 2.95→3.04 Å / % possible obs: 99.5 % / Redundancy: 4 % / Rmerge(I) obs: 1.619 / Num. measured all: 18249 / Num. unique obs: 4534 / CC1/2: 0.332 / Rpim(I) all: 0.905 / Rrim(I) all: 1.865 / Χ2: 1 / Net I/σ(I) obs: 0.8

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.18.2refinement
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.95→48.92 Å / SU ML: 0.53 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.252 1997 3.79 %
Rwork0.2162 --
obs0.2176 52717 99.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.95→48.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6370 0 55 0 6425
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0136561
X-RAY DIFFRACTIONf_angle_d1.5498899
X-RAY DIFFRACTIONf_dihedral_angle_d13.222915
X-RAY DIFFRACTIONf_chiral_restr0.076998
X-RAY DIFFRACTIONf_plane_restr0.011151
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.95-3.020.4341390.44323527X-RAY DIFFRACTION98
3.02-3.110.40241400.4073570X-RAY DIFFRACTION99
3.11-3.20.42941430.36743614X-RAY DIFFRACTION100
3.2-3.30.40041420.32263620X-RAY DIFFRACTION100
3.3-3.420.34991410.29783597X-RAY DIFFRACTION99
3.42-3.550.32781410.28333556X-RAY DIFFRACTION99
3.55-3.720.28871410.26433610X-RAY DIFFRACTION99
3.72-3.910.23751420.2323585X-RAY DIFFRACTION99
3.91-4.160.23961440.20283652X-RAY DIFFRACTION100
4.16-4.480.19411410.18033592X-RAY DIFFRACTION99
4.48-4.930.21031440.17283658X-RAY DIFFRACTION100
4.93-5.640.23931450.19793679X-RAY DIFFRACTION100
5.64-7.10.25311450.20543680X-RAY DIFFRACTION100
7.1-48.920.20421490.16273780X-RAY DIFFRACTION98

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