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- PDB-8fri: LSD1-CoREST in complex with AW4, short soaking -

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Basic information

Entry
Database: PDB / ID: 8fri
TitleLSD1-CoREST in complex with AW4, short soaking
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
KeywordsOXIDOREDUCTASE/INHIBITOR / Epigenetics / Histone demethylase / Drug resistance / Covalent inhibitor / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
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 / : / negative regulation of protein binding / 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 / 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 / positive regulation of cold-induced thermogenesis / regulation of protein localization / 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
: / Helical region in REST corepressor / : / ELM2 domain / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain profile. / ELM2 / SWIRM domain / SWIRM domain ...: / Helical region in REST corepressor / : / ELM2 domain / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain profile. / ELM2 / 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
: / Lysine-specific histone demethylase 1A / 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
DepositionJan 7, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 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)112,5833
Polymers111,5112
Non-polymers1,0721
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5340 Å2
ΔGint-43 kcal/mol
Surface area37620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.427, 178.992, 233.980
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: Chemical ChemComp-Y9K / [(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl (2R,3S,4S)-2,3,4-trihydroxy-5-[(1R,3S,3aS,13R)-1-hydroxy-10,11-dimethyl-4,6-dioxo-3-([1~1~,2~1~:2~3~,3~1~-terphenyl]-1~4~-yl)-2,3,5,6-tetrahydro-1H-benzo[g]pyrrolo[2,1-e]pteridin-8(4H)-yl]pentyl dihydrogen diphosphate (non-preferred name)


Mass: 1071.917 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C48H51N9O16P2 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.2 M Sodium/Potassium 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: 0.999869 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Jun 22, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999869 Å / Relative weight: 1
ReflectionResolution: 2.8→49.38 Å / Num. obs: 61215 / % possible obs: 99.7 % / Redundancy: 6.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.028 / Rrim(I) all: 0.073 / Χ2: 1.02 / Net I/σ(I): 17.3 / Num. measured all: 423392
Reflection shellResolution: 2.8→2.87 Å / % possible obs: 99.8 % / Redundancy: 7 % / Rmerge(I) obs: 1.536 / Num. measured all: 31133 / Num. unique obs: 4473 / CC1/2: 0.668 / Rpim(I) all: 0.624 / Rrim(I) all: 1.66 / Χ2: 1.02 / Net I/σ(I) obs: 1.4

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.18.2refinement
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→49.38 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2412 2000 3.27 %
Rwork0.2157 --
obs0.2166 61184 99.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.8→49.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 75 0 6368
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0116506
X-RAY DIFFRACTIONf_angle_d1.3778832
X-RAY DIFFRACTIONf_dihedral_angle_d11.726929
X-RAY DIFFRACTIONf_chiral_restr0.072989
X-RAY DIFFRACTIONf_plane_restr0.0081141
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.870.40111400.38314157X-RAY DIFFRACTION100
2.87-2.950.34361430.34314215X-RAY DIFFRACTION100
2.95-3.030.36291420.31394200X-RAY DIFFRACTION100
3.03-3.130.32011410.29934163X-RAY DIFFRACTION100
3.13-3.240.29831410.28234203X-RAY DIFFRACTION100
3.24-3.370.28941430.26124219X-RAY DIFFRACTION100
3.37-3.530.30291410.25074183X-RAY DIFFRACTION99
3.53-3.710.30031430.2464212X-RAY DIFFRACTION100
3.71-3.950.24541420.22774213X-RAY DIFFRACTION100
3.95-4.250.27321430.21344245X-RAY DIFFRACTION100
4.25-4.680.20551440.18474258X-RAY DIFFRACTION100
4.68-5.350.21731420.18984214X-RAY DIFFRACTION99
5.35-6.740.21741460.21024291X-RAY DIFFRACTION100
6.74-49.380.18191490.16924411X-RAY DIFFRACTION99

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