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- PDB-6w4k: Crystal structure of Lysine Specific Demethylase 1 (LSD1) with CC... -

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Basic information

Entry
Database: PDB / ID: 6w4k
TitleCrystal structure of Lysine Specific Demethylase 1 (LSD1) with CC-90011
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
KeywordsFLAVOPROTEIN / Human LSD1 Inhibitor-complex
Function / homology
Function and homology information


positive regulation of megakaryocyte differentiation / 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 / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development ...positive regulation of megakaryocyte differentiation / 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 / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development / positive regulation of neural precursor cell proliferation / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / MRF binding / regulation of androgen receptor signaling pathway / DNA repair complex / nuclear androgen receptor binding / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of double-strand break repair via homologous recombination / positive regulation of neuroblast proliferation / DNA repair-dependent chromatin remodeling / positive regulation of stem cell proliferation / histone H3K9 demethylase activity / histone deacetylase complex / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone methyltransferase complex / histone demethylase activity / positive regulation of cell size / positive regulation of epithelial to mesenchymal transition / response to fungicide / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / transcription repressor complex / epigenetic regulation of gene expression / cellular response to cAMP / positive regulation of protein ubiquitination / Regulation of PTEN gene transcription / erythrocyte differentiation / HDACs deacetylate histones / promoter-specific chromatin binding / cellular response to gamma radiation / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / positive regulation of neuron projection development / cerebral cortex development / protein modification process / 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 / chromatin organization / 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 / oxidoreductase activity / chromosome, telomeric region / negative regulation of gene expression / negative regulation of DNA-templated transcription / 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
: / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / SWIRM domain / SWIRM domain ...: / 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 / 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 / Chem-V0Y / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.93 Å
AuthorsHosfield, D.J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1).
Authors: Kanouni, T. / Severin, C. / Cho, R.W. / Yuen, N.Y. / Xu, J. / Shi, L. / Lai, C. / Del Rosario, J.R. / Stansfield, R.K. / Lawton, L.N. / Hosfield, D. / O'Connell, S. / Kreilein, M.M. / ...Authors: Kanouni, T. / Severin, C. / Cho, R.W. / Yuen, N.Y. / Xu, J. / Shi, L. / Lai, C. / Del Rosario, J.R. / Stansfield, R.K. / Lawton, L.N. / Hosfield, D. / O'Connell, S. / Kreilein, M.M. / Tavares-Greco, P. / Nie, Z. / Kaldor, S.W. / Veal, J.M. / Stafford, J.A. / Chen, Y.K.
History
DepositionMar 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,7744
Polymers88,5372
Non-polymers1,2372
Water39622
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6530 Å2
ΔGint-43 kcal/mol
Surface area36710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.655, 178.510, 236.049
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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


Mass: 73376.914 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, Oxidoreductases
#2: Protein REST corepressor 1 / Protein CoREST


Mass: 15160.241 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-V0Y / 4-[2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluorobenzonitrile


Mass: 451.469 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23F2N5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: H2O
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: 7.24 Å3/Da / Density % sol: 83 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.3M Na Tartrate

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Data collection

DiffractionMean temperature: 80 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17B1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Jan 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.93→50 Å / Num. obs: 55358 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.032 / Rrim(I) all: 0.083 / Χ2: 1.011 / Net I/σ(I): 6.8 / Num. measured all: 367961
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.93-3.036.50.90254710.830.3810.981.02299.9
3.03-3.166.20.61154670.9040.2680.6681.044100
3.16-3.36.90.41354950.9630.1690.4461.041100
3.3-3.4770.2555040.9840.1010.271.044100
3.47-3.696.90.16754870.9910.0680.1811.055100
3.69-3.986.70.10555020.9960.0440.1141.044100
3.98-4.386.50.06455070.9980.0270.070.983100
4.38-5.0170.04955700.9990.020.0530.995100
5.01-6.316.40.04655790.9990.020.050.922100
6.31-506.50.03357760.9990.0140.0360.95699.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
HKL-3000data reduction
HKL-3000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3zmu

3zmu


Resolution: 2.93→49.27 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.933 / SU B: 12.55 / SU ML: 0.211 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.271 / ESU R Free: 0.242 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2352 2723 4.9 %RANDOM
Rwork0.1914 ---
obs0.1936 52530 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 218.13 Å2 / Biso mean: 89.562 Å2 / Biso min: 45.34 Å2
Baniso -1Baniso -2Baniso -3
1-9.99 Å20 Å2-0 Å2
2---5.79 Å20 Å2
3----4.21 Å2
Refinement stepCycle: final / Resolution: 2.93→49.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6115 0 86 22 6223
Biso mean--70.42 66.33 -
Num. residues----776
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0136333
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175916
X-RAY DIFFRACTIONr_angle_refined_deg1.9411.6518593
X-RAY DIFFRACTIONr_angle_other_deg1.3161.57813737
X-RAY DIFFRACTIONr_dihedral_angle_1_deg9.3655772
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.42622.667330
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.663151095
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.1021541
X-RAY DIFFRACTIONr_chiral_restr0.0810.2813
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.027030
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021285
LS refinement shellResolution: 2.93→3.004 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.413 206 -
Rwork0.402 3639 -
obs--94.7 %

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