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- PDB-5lhi: Structure of the KDM1A/CoREST complex with the inhibitor N-[3-(et... -

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Basic information

Entry
Database: PDB / ID: 5lhi
TitleStructure of the KDM1A/CoREST complex with the inhibitor N-[3-(ethoxymethyl)-2-[[4-[[(3R)-pyrrolidin-3-yl]methoxy]phenoxy]methyl]phenyl]-4-methylthieno[3,2-b]pyrrole-5-carboxamide
Components
  • LYSINE-SPECIFIC HISTONE DEMETHYLASE 1
  • REST corepressor 1
KeywordsOXIDOREDUCTASE / Histone demethylase / inhibitor / complex
Function / homology
Function and homology information


positive regulation of megakaryocyte differentiation / guanine metabolic process / : / 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 / muscle cell development ...positive regulation of megakaryocyte differentiation / guanine metabolic process / : / 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 / muscle cell development / neuron maturation / positive regulation of neural precursor cell proliferation / regulation of androgen receptor signaling pathway / MRF binding / DNA repair complex / DNA repair-dependent chromatin remodeling / nuclear androgen receptor binding / regulation of double-strand break repair via homologous recombination / positive regulation of neuroblast proliferation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / positive regulation of stem cell proliferation / negative regulation of DNA binding / histone H3K9 demethylase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / histone deacetylase complex / positive regulation of cell size / histone demethylase activity / positive regulation of epithelial to mesenchymal transition / response to fungicide / cellular response to cAMP / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / transcription repressor complex / erythrocyte differentiation / nuclear receptor coactivator activity / positive regulation of protein ubiquitination / negative regulation of protein binding / Regulation of PTEN gene transcription / HDACs deacetylate histones / promoter-specific chromatin binding / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / negative regulation of DNA-binding transcription factor activity / 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 / positive regulation of cold-induced thermogenesis / chromatin organization / regulation of protein localization / Factors involved in megakaryocyte development and platelet production / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription regulator complex / Potential therapeutics for SARS / chromosome, telomeric region / transcription coactivator activity / oxidoreductase activity / chromatin remodeling / negative regulation of gene expression / negative regulation of DNA-templated transcription / chromatin binding / chromatin / regulation of transcription by RNA polymerase II / negative regulation of transcription by RNA polymerase II / enzyme binding / 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 / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1880 / : / Helical region in REST corepressor / : / ELM2 domain / ELM2 domain / ELM2 domain profile. / ELM2 / Histone lysine-specific demethylase / ATP synthase, gamma subunit, helix hairpin domain / SWIRM domain / SWIRM domain / SWIRM domain profile. / : / SANT domain profile. / SANT domain / Amine oxidase / Flavin containing amine oxidoreductase / 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-6X5 / 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: 3.4 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 12, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: LYSINE-SPECIFIC HISTONE DEMETHYLASE 1
B: REST corepressor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)147,6036
Polymers146,1132
Non-polymers1,4894
Water34219
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6980 Å2
ΔGint-48 kcal/mol
Surface area37070 Å2
MethodPISA
Unit cell
Length a, b, c (Å)120.030, 180.370, 235.750
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 1


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) / References: UniProt: O60341
#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, 23 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-6X5 / ~{N}-[3-(ethoxymethyl)-2-[[4-[[(3~{R})-pyrrolidin-3-yl]methoxy]phenoxy]methyl]phenyl]-4-methyl-thieno[3,2-b]pyrrole-5-carboxamide


Mass: 519.655 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H33N3O4S
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 19 / Source method: isolated from a natural source / Formula: H2O

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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: 4.37 Å3/Da / Density % sol: 71.83 %
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: 1,000
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jun 26, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
201
ReflectionResolution: 3.4→72.04 Å / Num. obs: 35457 / % possible obs: 100 % / Redundancy: 4.5 % / Rmerge(I) obs: 0.118 / Net I/σ(I): 11.2

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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: 3.4→72.04 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.17
RfactorNum. reflection% reflection
Rfree0.225 1772 5 %
Rwork0.1953 --
obs0.1967 35446 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.4→72.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6289 0 102 19 6410
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0056527
X-RAY DIFFRACTIONf_angle_d0.9238854
X-RAY DIFFRACTIONf_dihedral_angle_d13.8623934
X-RAY DIFFRACTIONf_chiral_restr0.055985
X-RAY DIFFRACTIONf_plane_restr0.0051138
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.4-3.49190.32971440.30942537X-RAY DIFFRACTION100
3.4919-3.59470.35771320.28082550X-RAY DIFFRACTION100
3.5947-3.71070.35271220.26922598X-RAY DIFFRACTION100
3.7107-3.84330.27471320.25922547X-RAY DIFFRACTION100
3.8433-3.99720.24841370.21432580X-RAY DIFFRACTION100
3.9972-4.17910.25191230.19472573X-RAY DIFFRACTION100
4.1791-4.39940.20081320.18172570X-RAY DIFFRACTION100
4.3994-4.6750.19131420.16852567X-RAY DIFFRACTION99
4.675-5.03590.19891370.15532587X-RAY DIFFRACTION100
5.0359-5.54250.21041490.17772598X-RAY DIFFRACTION100
5.5425-6.34410.24721280.19452622X-RAY DIFFRACTION100
6.3441-7.99120.20651490.18712633X-RAY DIFFRACTION100
7.9912-72.05890.17431450.16922712X-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)
11.37490.0535-0.0962.1584-0.38643.6325-0.0982-0.01630.28470.1668-0.2191-0.3852-0.39550.73230.33890.6487-0.1041-0.11870.61220.23860.624411.3083-54.3613-20.4179
21.4803-4.46432.75993.8315-3.84012.26020.1531-0.16550.4056-0.5272-0.2896-0.90630.16940.04710.22371.40120.2061-0.40930.87950.52541.4275-29.3658-7.5164-62.9675
31.73320.1033-0.37013.2585-0.72883.6743-0.07480.2984-0.105-0.2731-0.3544-0.2510.13210.36810.41190.66540.0651-0.00180.46750.08980.48613.4604-64.0919-32.7867
49.09363.85784.30284.86393.39227.6767-0.4385-0.41390.4519-0.45030.12641.1898-1.2208-1.25990.14070.98980.0219-0.31840.83540.21651.2288-19.4411-37.0076-38.4053
51.6669-0.7610.16317.4195-3.01971.8285-0.166-0.1192-0.0161-0.2428-0.0857-0.85950.35140.06810.37361.09240.0563-0.39291.03340.30181.0891-28.6682-15.2576-66.0855
62.86010.3537-3.16313.8921-0.64393.52510.1865-1.1049-0.53031.84050.7425-1.18340.24920.4548-0.37891.4876-0.0975-0.51641.09550.21160.7928-41.935125.3566-61.407
77.18520.13220.5362.6238-0.72832.0064-0.541-1.92610.31712.597-0.7602-0.0084-0.8892-0.7740.86411.87740.0629-0.00011.7241-0.07430.8197-52.060424.6168-55.542
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 171 through 407 )
2X-RAY DIFFRACTION2chain 'A' and (resid 408 through 522 )
3X-RAY DIFFRACTION3chain 'A' and (resid 523 through 836 )
4X-RAY DIFFRACTION4chain 'B' and (resid 308 through 329 )
5X-RAY DIFFRACTION5chain 'B' and (resid 330 through 377 )
6X-RAY DIFFRACTION6chain 'B' and (resid 378 through 417 )
7X-RAY DIFFRACTION7chain 'B' and (resid 418 through 440 )

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