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- PDB-4uv9: LSD1(KDM1A)-CoREST in complex with 1-Ethyl-Tranylcypromine -

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Basic information

Entry
Database: PDB / ID: 4uv9
TitleLSD1(KDM1A)-CoREST in complex with 1-Ethyl-Tranylcypromine
Components
  • LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A
  • REST COREPRESSOR 1RCOR1
KeywordsTRANSCRIPTION / COVALENT INHIBITOR
Function / homology
Function and homology information


HDACs deacetylate histones / HDMs demethylate histones / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Regulation of PTEN gene transcription / Estrogen-dependent gene expression / Factors involved in megakaryocyte development and platelet production / muscle cell development / guanine metabolic process / positive regulation of histone ubiquitination / demethylase activity ...HDACs deacetylate histones / HDMs demethylate histones / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Regulation of PTEN gene transcription / Estrogen-dependent gene expression / Factors involved in megakaryocyte development and platelet production / muscle cell development / guanine metabolic process / positive regulation of histone ubiquitination / demethylase activity / protein demethylation / telomeric repeat-containing RNA binding / DNA repair complex / positive regulation of stem cell proliferation / neuron maturation / alternative mRNA splicing, via spliceosome / negative regulation of histone H3-K9 methylation / negative regulation of histone H3-K4 methylation / positive regulation of neural precursor cell proliferation / histone demethylase activity (H3-K4 specific) / positive regulation of cell size / histone H4 deacetylation / histone demethylase activity (H3-dimethyl-K4 specific) / MRF binding / histone H3-K4 demethylation / positive regulation of neuroblast proliferation / 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 / telomeric DNA binding / transcriptional repressor complex / ec:1.-.-.-: / positive regulation of chromatin binding / negative regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of DNA binding / regulation of cellular protein localization / histone demethylase activity (H3-K9 specific) / histone H3-K9 demethylation / response to fungicide / histone demethylase activity / androgen receptor binding / positive regulation of neuron projection development / cerebral cortex development / cellular response to cAMP / DNA-binding transcription repressor activity, RNA polymerase II-specific / cellular response to UV / cellular response to gamma radiation / RNA polymerase II transcription factor binding / negative regulation of protein binding / positive regulation of cold-induced thermogenesis / nuclear receptor transcription coactivator activity / negative regulation of DNA-binding transcription factor activity / p53 binding / transcription regulatory region DNA binding / transcription factor complex / nuclear chromosome, telomeric region / positive regulation of DNA-binding transcription factor activity / flavin adenine dinucleotide binding / nuclear chromatin / blood coagulation / oxidoreductase activity / regulation of transcription by RNA polymerase II / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription factor binding / negative regulation of transcription, DNA-templated / chromatin binding / DNA-binding transcription factor activity / viral process / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / nucleus
ELM2 domain / SANT domain profile. / Myb-like DNA-binding domain / ELM2 domain / SANT/Myb domain / SANT domain / Flavin containing amine oxidoreductase / SWIRM domain / Histone lysine-specific demethylase / SWIRM domain profile. ...ELM2 domain / SANT domain profile. / Myb-like DNA-binding domain / ELM2 domain / SANT/Myb domain / SANT domain / Flavin containing amine oxidoreductase / SWIRM domain / Histone lysine-specific demethylase / SWIRM domain profile. / ELM2 domain profile. / Winged helix-like DNA-binding domain superfamily / Homeobox-like domain superfamily / SWIRM domain / Amine oxidase / FAD/NAD(P)-binding domain superfamily
Lysine-specific histone demethylase 1A / REST corepressor 1
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsVianello, P. / Botrugno, O. / Cappa, A. / Ciossani, G. / Dessanti, P. / Mai, A. / Mattevi, A. / Meroni, G. / Minucci, S. / Thaler, F. / Tortorici, M. / Trifiro, P. / Valente, S. / Villa, M. / Varasi, M. / Mercurio, C.
CitationJournal: Eur.J.Med.Chem. / Year: 2014
Title: Synthesis, Biological Activity and Mechanistic Insights of 1-Substituted Cyclopropylamine Derivatives: A Novel Class of Irreversible Inhibitors of Histone Demethylase Kdm1A.
Authors: Vianello, P. / Botrugno, O.A. / Cappa, A. / Ciossani, G. / Dessanti, P. / Mai, A. / Mattevi, A. / Meroni, G. / Minucci, S. / Thaler, F. / Tortorici, M. / Trifiro, P. / Valente, S. / Villa, M. / Varasi, M. / Mercurio, C.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Aug 5, 2014 / Release: Sep 10, 2014
RevisionDateData content typeProviderType
1.0Sep 10, 2014Structure modelrepositoryInitial 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)148,8973
Polymers147,9482
Non-polymers9491
Water0
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6810 Å2
ΔGint-47.5 kcal/mol
Surface area37580 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)118.300, 178.560, 234.020
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/peptide LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A / BRAF35-HDAC COMPLEX PROTEIN BHC110 / FLAVIN-CONTAINING AMINE OXIDASE DOMAIN-CONTAINING PROTEIN 2


Mass: 94846.234 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: O60341, EC: 1.-.-.-
#2: Protein/peptide REST COREPRESSOR 1 / RCOR1 / PROTEIN COREST


Mass: 53101.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: Q9UKL0
#3: Chemical ChemComp-D70 / [(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-[(4aS,10aS)-4a-[(1S,3E)-3-imino-1-phenylpentyl]-7,8-dimethyl-2,4-dioxo-1,3,4,4a,5,10a-hexahydrobenzo[g]pteridin-10(2H)-yl]pentyl dihydrogen diphosphate


Mass: 948.809 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H50N10O15P2

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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: 4.18 Å3/Da / Density % sol: 75 % / Description: NONE
Crystal growpH: 6.5 / Details: PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1
DetectorType: DECTRIS PIXEL / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→53 Å / Num. obs: 49581 / % possible obs: 99.5 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 7.5
Reflection shellResolution: 3→3.16 Å / Redundancy: 3.6 % / Rmerge(I) obs: 1.06 / Mean I/σ(I) obs: 1.3 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.7.0027refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2V1D
Resolution: 3→53.23 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.911 / SU B: 13.191 / SU ML: 0.231 / Cross valid method: THROUGHOUT / ESU R: 0.359 / ESU R Free: 0.269 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES - REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.24585 971 2 %RANDOM
Rwork0.22615 ---
Obs0.22654 48610 99.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 73.166 Å2
Baniso -1Baniso -2Baniso -3
1-4.22 Å20 Å20 Å2
2---2.83 Å20 Å2
3----1.38 Å2
Refinement stepCycle: LAST / Resolution: 3→53.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 65 0 6358
Refine LS restraints

Refinement-ID: X-RAY DIFFRACTION

TypeDev idealDev ideal targetNumber
r_bond_refined_d0.0050.0196493
r_bond_other_d
r_angle_refined_deg0.9761.9748806
r_angle_other_deg
r_dihedral_angle_1_deg4.8325797
r_dihedral_angle_2_deg35.27124.475295
r_dihedral_angle_3_deg16.938151130
r_dihedral_angle_4_deg13.6691542
r_chiral_restr0.060.2984
r_gen_planes_refined0.0030.0214889
r_gen_planes_other
r_nbd_refined
r_nbd_other
r_nbtor_refined
r_nbtor_other
r_xyhbond_nbd_refined
r_xyhbond_nbd_other
r_metal_ion_refined
r_metal_ion_other
r_symmetry_vdw_refined
r_symmetry_vdw_other
r_symmetry_hbond_refined
r_symmetry_hbond_other
r_symmetry_metal_ion_refined
r_symmetry_metal_ion_other
r_mcbond_it
r_mcbond_other
r_mcangle_it
r_mcangle_other
r_scbond_it
r_scbond_other
r_scangle_it
r_scangle_other
r_long_range_B_refined
r_long_range_B_other
r_rigid_bond_restr
r_sphericity_free
r_sphericity_bonded
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 80 -
Rwork0.351 3547 -
Obs--99.48 %

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