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

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Basic information

Entry
Database: PDB / ID: 5lgu
TitleThieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1: Compound 34
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 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 / 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 / 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 / positive regulation of neuron projection development / HDMs demethylate histones / 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 / DNA-binding transcription factor binding / Estrogen-dependent gene expression / 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
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-6W1 / 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 2: Structure-Based Drug Design and Structure-Activity Relationship.
Authors: Vianello, P. / Sartori, L. / Amigoni, F. / Cappa, A. / Faga, G. / Fattori, R. / Legnaghi, E. / Ciossani, G. / Mattevi, A. / Meroni, G. / Moretti, L. / Cecatiello, V. / Pasqualato, S. / ...Authors: Vianello, P. / Sartori, L. / 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. / Botrugno, O.A. / Dessanti, P. / Minucci, S. / Vultaggio, S. / Zagarri, E. / Varasi, M. / Mercurio, C.
History
DepositionJul 8, 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)102,7714
Polymers101,5242
Non-polymers1,2472
Water00
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6690 Å2
ΔGint-50 kcal/mol
Surface area37910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.409, 181.155, 237.456
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: 81279.438 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: 20244.824 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-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#4: Chemical ChemComp-6W1 / 4-methyl-~{N}-[2-[[4-[[(3~{R})-pyrrolidin-3-yl]methoxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide


Mass: 461.576 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27N3O3S

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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: 6.43 Å3/Da / Density % sol: 80 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: The hanging-drop vapor diffusion method at 20 C by mixing equal volumes of 100 microM LSD1-CoREST solution in 5% (w/v) glycerol, 25 mm potassium phosphate, pH 7.2, with reservoir solutions ...Details: The hanging-drop vapor diffusion method at 20 C by mixing equal volumes of 100 microM LSD1-CoREST solution in 5% (w/v) glycerol, 25 mm potassium phosphate, pH 7.2, with reservoir solutions containing 1.2 M sodium/potassium tartrate and 100 mmN-(2-acetamido)-2-iminodiacetic acid, pH 6.5.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1.00004 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Apr 23, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 3.2→50 Å / Num. obs: 43214 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Redundancy: 5.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.096 / Net I/σ(I): 12.9
Reflection shellResolution: 3.2→3.32 Å / Redundancy: 5.2 % / Rmerge(I) obs: 0.926 / Mean I/σ(I) obs: 1.6 / CC1/2: 0.551 / % possible all: 97.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
iMOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2V1D

2v1d


Resolution: 3.2→50 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.952 / SU B: 15.396 / SU ML: 0.241 / Cross valid method: THROUGHOUT / ESU R: 0.366 / ESU R Free: 0.259 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20649 835 1.9 %RANDOM
Rwork0.18446 ---
obs0.18492 42378 99.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 101.407 Å2
Baniso -1Baniso -2Baniso -3
1-7.04 Å20 Å2-0 Å2
2---5.32 Å20 Å2
3----1.73 Å2
Refinement stepCycle: 1 / Resolution: 3.2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 86 0 6379
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0196517
X-RAY DIFFRACTIONr_bond_other_d0.0010.026300
X-RAY DIFFRACTIONr_angle_refined_deg1.3591.9778839
X-RAY DIFFRACTIONr_angle_other_deg0.782314486
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1155797
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.73124.475295
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.568151130
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0131542
X-RAY DIFFRACTIONr_chiral_restr0.0620.2985
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0217332
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021484
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_it5.0859.7553195
X-RAY DIFFRACTIONr_mcbond_other5.0859.7543196
X-RAY DIFFRACTIONr_mcangle_it7.98314.633989
X-RAY DIFFRACTIONr_mcangle_other7.98214.6293990
X-RAY DIFFRACTIONr_scbond_it5.18710.4433322
X-RAY DIFFRACTIONr_scbond_other5.18610.4423323
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.63215.3774851
X-RAY DIFFRACTIONr_long_range_B_refined12.37579.17770
X-RAY DIFFRACTIONr_long_range_B_other12.37479.17771
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
Rfree0.332 61 -
Rwork0.357 3036 -
obs--96.57 %

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