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- PDB-4uxn: LSD1(KDM1A)-CoREST in complex with Z-Pro derivative of MC2580 -

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Basic information

Entry
Database: PDB / ID: 4uxn
TitleLSD1(KDM1A)-CoREST in complex with Z-Pro derivative of MC2580
Components
  • LYSINE-SPECIFIC HISTONE DEMETHYLASE 1A
  • REST COREPRESSOR 1
KeywordsOXIDOREDUCTASE / COVALENT INHIBITOR / TRANYLCYPROMINE
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 / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation ...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 / FAD-dependent H3K4me/H3K4me3 demethylase activity / demethylase activity / telomeric repeat-containing RNA binding / histone H3K4 demethylase activity / neuron maturation / muscle cell development / 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 / epigenetic regulation of gene expression / Regulation of PTEN gene transcription / positive regulation of protein ubiquitination / HDACs deacetylate histones / negative regulation of DNA-binding transcription factor activity / promoter-specific chromatin binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / HDMs demethylate histones / 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 / regulation of protein localization / chromatin organization / positive regulation of cold-induced thermogenesis / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / transcription regulator complex / Estrogen-dependent gene expression / RNA polymerase II-specific DNA-binding transcription factor binding / 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
FLAVIN-ADENINE DINUCLEOTIDE / Chem-M8A / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.85 Å
AuthorsRodriguez, V. / Valente, S. / Stazi, G. / Lucidi, A. / Mercurio, C. / Vianello, P. / Ciossani, G. / Mattevi, A. / Botrugno, O.A. / Dessanti, P. ...Rodriguez, V. / Valente, S. / Stazi, G. / Lucidi, A. / Mercurio, C. / Vianello, P. / Ciossani, G. / Mattevi, A. / Botrugno, O.A. / Dessanti, P. / Minucci, S. / Varasi, M. / Mai, A.
CitationJournal: Chemmedchem / Year: 2015
Title: Pyrrole- and Indole-Containing Tranylcypromine Derivatives as Novel Lysine-Specific Demethylase 1 Inhibitors Active on Cancer Cells
Authors: Rodriguez, V. / Valente, S. / Rovida, S. / Rotili, D. / Stazi, G. / Lucidi, A. / Ciossani, G. / Mattevi, A. / Botrugno, O.A. / Dessanti, P. / Mercurio, C. / Vianello, P. / Minucci, S. / Varasi, M. / Mai, A.
History
DepositionAug 27, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 25, 2015Provider: repository / Type: Initial release
Revision 1.1Jun 13, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jun 20, 2018Group: Advisory / Data collection / Derived calculations / Category: pdbx_validate_close_contact / struct_conn
Revision 1.3Feb 20, 2019Group: Advisory / Data collection / Derived calculations
Category: pdbx_data_processing_status / pdbx_validate_close_contact / struct_conn
Item: _pdbx_data_processing_status.task_name
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf

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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)147,2794
Polymers146,1132
Non-polymers1,1662
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6620 Å2
ΔGint-43.4 kcal/mol
Surface area37190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.980, 177.760, 233.720
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: 93011.453 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, 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 (E. coli) / Strain (production host): BL21 / References: UniProt: Q9UKL0
#3: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#4: Chemical ChemComp-M8A / benzyl (2R)-2-{[4-(3-oxopropyl)phenyl]carbamoyl}pyrrolidine-1-carboxylate


Mass: 380.437 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24N2O4

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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: 77 % / 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: ID14 / Wavelength: 1
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→99 Å / Num. obs: 57587 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 3.1 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 6.9
Reflection shellResolution: 2.85→2.93 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.98 / Mean I/σ(I) obs: 1.4 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2V1D

2v1d


Resolution: 2.85→141.49 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.946 / SU B: 11.959 / SU ML: 0.204 / Cross valid method: THROUGHOUT / ESU R: 0.27 / ESU R Free: 0.208 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.21509 1103 1.9 %RANDOM
Rwork0.20615 ---
obs0.20633 56375 98.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.9 Å2
Baniso -1Baniso -2Baniso -3
1-7.07 Å20 Å20 Å2
2---4.16 Å20 Å2
3----2.92 Å2
Refinement stepCycle: LAST / Resolution: 2.85→141.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 81 0 6374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0196511
X-RAY DIFFRACTIONr_bond_other_d0.0030.026297
X-RAY DIFFRACTIONr_angle_refined_deg2.1641.9768827
X-RAY DIFFRACTIONr_angle_other_deg1.0323.00114481
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6955797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.37824.475295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg23.878151130
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.4011542
X-RAY DIFFRACTIONr_chiral_restr0.10.2985
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0217327
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021479
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_it7.2917.3233197
X-RAY DIFFRACTIONr_mcbond_other7.2837.3223196
X-RAY DIFFRACTIONr_mcangle_it10.52110.9843991
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it8.7238.2773314
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: 2.85→2.924 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.472 68 -
Rwork0.434 4138 -
obs--98.89 %

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