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- PDB-5lgn: Thieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 5lgn
TitleThieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1: Compound 19
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
KeywordsOXIDOREDUCTASE
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
Chem-6W0 / FLAVIN-ADENINE DINUCLEOTIDE / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3.2 Å
AuthorsMattevi, A. / Ciossani, G.
Funding support Italy, 1items
OrganizationGrant numberCountry
AIRCIG15208 Italy
CitationJournal: J. Med. Chem. / Year: 2017
Title: Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration.
Authors: Sartori, L. / Mercurio, C. / Amigoni, F. / Cappa, A. / Faga, G. / Fattori, R. / Legnaghi, E. / Ciossani, G. / Mattevi, A. / Meroni, G. / Moretti, L. / Cecatiello, V. / Pasqualato, S. / ...Authors: Sartori, L. / Mercurio, C. / Amigoni, F. / Cappa, A. / Faga, G. / Fattori, R. / Legnaghi, E. / Ciossani, G. / Mattevi, A. / Meroni, G. / Moretti, L. / Cecatiello, V. / Pasqualato, S. / Romussi, A. / Thaler, F. / Trifiro, P. / Villa, M. / Vultaggio, S. / Botrugno, O.A. / Dessanti, P. / Minucci, S. / Zagarri, E. / Carettoni, D. / Iuzzolino, L. / Varasi, M. / Vianello, P.
History
DepositionJul 7, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)90,9894
Polymers89,9032
Non-polymers1,0862
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6710 Å2
ΔGint-47 kcal/mol
Surface area38070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.510, 180.440, 235.420
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: 74585.266 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The FAD cofactor is integral part of the protein chain
Source: (gene. exp.) Homo sapiens (human) / Gene: KDM1A, AOF2, KDM1, KIAA0601, LSD1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: O60341, Oxidoreductases
#2: Protein REST corepressor 1 / Protein CoREST


Mass: 15317.435 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) / Strain (production host): BL21 / References: UniProt: Q9UKL0
#3: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C27H33N9O15P2
Details: The FAD cofactor is integral part of the protein chain
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / Comment: FAD*YM
#4: Chemical ChemComp-6W0 / ~{N}-[3-(methoxymethyl)phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide


Mass: 300.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N2O2S

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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 % sol: 80 %
Crystal growTemperature: 297 K / Method: vapor diffusion / pH: 5.6
Details: Sodium Tartrate 1.2 M as precipitant in Sodium Citrate buffer pH 5.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 1 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.2→80 Å / Num. obs: 42318 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Redundancy: 4.1 % / CC1/2: 0.993 / Rmerge(I) obs: 0.151 / Net I/σ(I): 4.3
Reflection shellResolution: 3.2→3.32 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.993 / Mean I/σ(I) obs: 0.7 / CC1/2: 0.37 / % possible all: 99.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
iMOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4BAY

4bay


Resolution: 3.2→80 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.93 / SU B: 19.787 / SU ML: 0.3 / Cross valid method: THROUGHOUT / ESU R: 0.405 / ESU R Free: 0.282 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22017 811 1.9 %RANDOM
Rwork0.19321 ---
obs0.19379 40986 97.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 114.712 Å2
Baniso -1Baniso -2Baniso -3
1-8.22 Å20 Å2-0 Å2
2---3.08 Å2-0 Å2
3----5.14 Å2
Refinement stepCycle: 1 / Resolution: 3.2→80 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6325 0 74 0 6399
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0196535
X-RAY DIFFRACTIONr_bond_other_d0.0020.026319
X-RAY DIFFRACTIONr_angle_refined_deg1.3411.9778867
X-RAY DIFFRACTIONr_angle_other_deg0.7683.00114530
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4235801
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.67724.512297
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.815151137
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8621542
X-RAY DIFFRACTIONr_chiral_restr0.0640.2989
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0217374
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021482
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_it6.64711.0143210
X-RAY DIFFRACTIONr_mcbond_other6.64611.0143209
X-RAY DIFFRACTIONr_mcangle_it10.41916.5174009
X-RAY DIFFRACTIONr_mcangle_other10.41816.5184010
X-RAY DIFFRACTIONr_scbond_it6.72311.843325
X-RAY DIFFRACTIONr_scbond_other6.72211.843326
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other11.1417.4164859
X-RAY DIFFRACTIONr_long_range_B_refined14.92188.7637664
X-RAY DIFFRACTIONr_long_range_B_other14.92188.7657665
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.2→3.283 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.432 53 -
Rwork0.393 2898 -
obs--95.44 %

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