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- PDB-4uvc: LSD1(KDM1A)-CoREST in complex with 1-Phenyl-Tranylcypromine -

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Basic information

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


positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / [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 / muscle cell development ...positive regulation of megakaryocyte differentiation / guanine metabolic process / negative regulation of transcription initiation-coupled chromatin remodeling / protein demethylation / [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 / muscle cell development / neuron maturation / positive regulation of neural precursor cell proliferation / MRF binding / regulation of androgen receptor signaling pathway / DNA repair complex / negative regulation of DNA binding / 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 / positive regulation of stem cell proliferation / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase 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 / cellular response to cAMP / 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 / 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 / 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 / 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 / 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
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / ATP synthase, gamma subunit, helix hairpin domain ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / Histone lysine-specific demethylase / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / ATP synthase, gamma subunit, helix hairpin domain / 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 / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Homeobox-like domain superfamily / FAD/NAD(P)-binding domain superfamily / Helix Hairpins / Arc Repressor Mutant, subunit A / Winged helix-like DNA-binding domain superfamily / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-D52 / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsVianello, P. / Botrugno, O. / Cappa, A. / Ciossani, G. / Dessanti, P. / Mai, A. / Mattevi, A. / Meroni, G. / Minucci, S. / Thaler, F. ...Vianello, 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. ...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.
History
DepositionAug 5, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 10, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)148,9453
Polymers147,9482
Non-polymers9971
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6740 Å2
ΔGint-50.1 kcal/mol
Surface area37870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.960, 179.090, 234.800
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


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 BL21 (bacteria) / References: UniProt: O60341, Oxidoreductases
#2: Protein REST COREPRESSOR 1 / 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 BL21 (bacteria) / References: UniProt: Q9UKL0
#3: Chemical ChemComp-D52 / [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2R,3S,4S)-5-[5-[(1S)-1-azanyl-1,3-diphenyl-propyl]-7,8-dimethyl-2,4-bis(oxidanylidene)-4aH-benzo[g]pteridin-10-yl]-2,3,4-tris(oxidanyl)pentyl] hydrogen phosphate


Mass: 996.852 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H50N10O15P2

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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: 4.23 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: SLS / Beamline: X06SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→60 Å / Num. obs: 45854 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 6.1 % / Rmerge(I) obs: 0.19 / Net I/σ(I): 9
Reflection shellResolution: 3.1→3.27 Å / Redundancy: 5.6 % / Rmerge(I) obs: 1.32 / Mean I/σ(I) obs: 1.2 / % possible all: 99.9

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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

2v1d


Resolution: 3.1→68.53 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.898 / SU B: 13.683 / SU ML: 0.232 / Cross valid method: THROUGHOUT / ESU R: 0.375 / ESU R Free: 0.283 / 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
Rfree0.24114 887 1.9 %RANDOM
Rwork0.21031 ---
obs0.21094 44967 99.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 87.094 Å2
Baniso -1Baniso -2Baniso -3
1-6.28 Å20 Å20 Å2
2---4.38 Å20 Å2
3----1.9 Å2
Refinement stepCycle: LAST / Resolution: 3.1→68.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6292 0 69 0 6361
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0196496
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0971.9758810
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0265797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.39524.475295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.495151130
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.851542
X-RAY DIFFRACTIONr_chiral_restr0.0690.2985
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0214892
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.1→3.18 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.345 65 -
Rwork0.361 3311 -
obs--99.88 %

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