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- PDB-5lhg: Structure of the KDM1A/CoREST complex with the inhibitor 4-methyl... -

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Basic information

Entry
Database: PDB / ID: 5lhg
TitleStructure of the KDM1A/CoREST complex with the inhibitor 4-methyl-N-[4-[[4-(1-methylpiperidin-4-yl)oxyphenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide
Components
  • Lysine-specific histone demethylase 1A
  • REST corepressor 1
KeywordsOXIDOREDUCTASE / Histone demethylase / inhibitor / complex
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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone methyltransferase complex / 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 / transcription repressor complex / cellular response to cAMP / epigenetic regulation of gene expression / 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 / HDMs demethylate histones / positive regulation of neuron projection development / cerebral cortex development / protein modification process / cellular response to UV / p53 binding / 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 / 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-6X3 / FLAVIN-ADENINE DINUCLEOTIDE / Lysine-specific histone demethylase 1A / REST corepressor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.34 Å
AuthorsCecatiello, V. / Pasqualato, S.
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 11, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2017Group: Database references
Revision 1.2Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.3Jan 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
Revision 1.4Oct 1, 2025Group: Advisory / Derived calculations / Structure summary
Category: pdbx_entry_details / pdbx_validate_close_contact / struct_conn

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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)148,2199
Polymers146,1132
Non-polymers2,1057
Water36020
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7590 Å2
ΔGint-47 kcal/mol
Surface area37700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.360, 180.580, 234.580
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

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Protein , 2 types, 2 molecules AB

#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) / Gene: KDM1A, AOF2, KDM1, KIAA0601, LSD1 / Production host: Escherichia coli (E. coli) / 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) / Gene: RCOR1, KIAA0071, RCOR / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UKL0

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Non-polymers , 4 types, 27 molecules

#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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-6X3 / 4-methyl-N-[4-[[4-[(1-methyl-4-piperidyl)oxy]phenoxy]methyl]phenyl]thieno[3,2-b]pyrrole-5-carboxamide


Mass: 475.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H29N3O3S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationN

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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: 4.36 Å3/Da / Density % sol: 71.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 1.1-1.2 M Na/K tartrate 0.1 M ADA pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 17, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.34→71.76 Å / Num. obs: 37430 / % possible obs: 100 % / Redundancy: 9 % / Rmerge(I) obs: 0.138 / Net I/σ(I): 14.2

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
XDSdata reduction
xia2data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2V1D

2v1d


Resolution: 3.34→69.028 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.79
RfactorNum. reflection% reflection
Rfree0.1924 1935 5.17 %
Rwork0.157 --
obs0.1588 37413 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.34→69.028 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6293 0 145 20 6458
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0026577
X-RAY DIFFRACTIONf_angle_d0.4718918
X-RAY DIFFRACTIONf_dihedral_angle_d11.2913954
X-RAY DIFFRACTIONf_chiral_restr0.039986
X-RAY DIFFRACTIONf_plane_restr0.0021142
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.34-3.42350.32341430.26012478X-RAY DIFFRACTION100
3.4235-3.51610.28131330.23842499X-RAY DIFFRACTION100
3.5161-3.61960.27211420.21692513X-RAY DIFFRACTION100
3.6196-3.73640.23881420.20722486X-RAY DIFFRACTION100
3.7364-3.86990.27351300.19252521X-RAY DIFFRACTION100
3.8699-4.02480.18981420.16812520X-RAY DIFFRACTION100
4.0248-4.2080.17641340.14922505X-RAY DIFFRACTION100
4.208-4.42980.14731600.12872525X-RAY DIFFRACTION100
4.4298-4.70730.16581350.12352526X-RAY DIFFRACTION100
4.7073-5.07070.14041150.11572543X-RAY DIFFRACTION100
5.0707-5.58070.15531350.1372549X-RAY DIFFRACTION100
5.5807-6.38780.18921270.16142578X-RAY DIFFRACTION100
6.3878-8.0460.19221330.15532582X-RAY DIFFRACTION100
8.046-69.04310.18211640.13992653X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.67440.1516-0.42531.6275-0.16234.3783-0.0449-0.10720.32660.2229-0.1608-0.6269-0.5720.7750.22990.7657-0.0971-0.20810.64790.20080.723715.265-57.0192-17.2133
21.9213-4.52282.29186.5002-3.96082.0067-0.03170.24850.42140.1247-0.2924-0.3053-0.19250.09450.32171.06740.0578-0.31830.76790.27881.1243-19.8367-23.4467-52.8988
32.1877-0.1714-0.28763.4672-0.95263.6244-0.07130.30390.0106-0.2313-0.3067-0.3640.14710.26580.3630.63750.0303-0.01420.42750.06020.47824.0331-67.1603-31.8989
46.06724.22192.09086.76493.0087.7288-0.0186-0.32860.0973-0.66450.42981.0246-0.8546-1.2013-0.36231.2699-0.0235-0.40381.01240.3741.1902-19.9028-37.3693-38.3437
54.7855-4.93734.6026.5555-5.74174.89950.50160.351-0.1597-1.44640.09480.82551.0078-0.4468-0.70790.92580.1143-0.10510.81320.17550.8634-28.8239-21.8755-64.9111
64.86281.08980.38390.4074-0.42642.53-0.0757-2.0425-0.06180.29830.5808-2.0061-0.62871.315-0.50331.1409-0.256-0.28141.13390.19021.2988-32.973525.8677-66.096
71.9602-1.28350.29067.88211.50012.0376-0.4401-1.8484-0.20671.93060.1141-0.29120.44830.34760.31241.35580.0535-0.22411.21060.11640.6441-46.787323.6927-58.0554
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 171 through 371 )
2X-RAY DIFFRACTION2chain 'A' and (resid 372 through 564 )
3X-RAY DIFFRACTION3chain 'A' and (resid 565 through 836 )
4X-RAY DIFFRACTION4chain 'B' and (resid 308 through 329 )
5X-RAY DIFFRACTION5chain 'B' and (resid 330 through 370 )
6X-RAY DIFFRACTION6chain 'B' and (resid 371 through 384 )
7X-RAY DIFFRACTION7chain 'B' and (resid 385 through 440 )

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