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Yorodumi- PDB-5lgt: Thieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitor... -
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-Basic information
Entry | Database: PDB / ID: 5lgt | ||||||
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Title | Thieno[3,2-b]pyrrole-5-carboxamides as Novel Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1: Compound 15 | ||||||
Components |
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Keywords | OXIDOREDUCTASE | ||||||
Function / homology | Function and homology information positive regulation of megakaryocyte differentiation / guanine metabolic process / regulation of DNA methylation-dependent heterochromatin formation / 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 / regulation of DNA methylation-dependent heterochromatin formation / 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 / cellular response to cAMP / response to fungicide / NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux / Regulation of PTEN gene transcription / transcription repressor complex / erythrocyte differentiation / nuclear receptor coactivator activity / positive regulation of protein ubiquitination / negative regulation of protein binding / HDACs deacetylate histones / promoter-specific chromatin binding / HDMs demethylate histones / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / negative regulation of DNA-binding transcription factor activity / p53 binding / cellular response to gamma radiation / cerebral cortex development / positive regulation of neuron projection development / transcription corepressor activity / regulation of protein localization / cellular response to UV / Factors involved in megakaryocyte development and platelet production / chromatin organization / positive regulation of cold-induced thermogenesis / flavin adenine dinucleotide binding / chromosome, telomeric region / DNA-binding transcription factor binding / Potential therapeutics for SARS / transcription regulator complex / Estrogen-dependent gene expression / transcription coactivator activity / RNA polymerase II-specific DNA-binding transcription factor binding / oxidoreductase activity / chromatin remodeling / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3 Å | ||||||
Authors | Mattevi, A. / Ciossani, G. | ||||||
Funding support | Italy, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5lgt.cif.gz | 178.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb5lgt.ent.gz | 135.2 KB | Display | PDB format |
PDBx/mmJSON format | 5lgt.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 5lgt_validation.pdf.gz | 1 MB | Display | wwPDB validaton report |
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Full document | 5lgt_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 5lgt_validation.xml.gz | 30.7 KB | Display | |
Data in CIF | 5lgt_validation.cif.gz | 41.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/lg/5lgt ftp://data.pdbj.org/pub/pdb/validation_reports/lg/5lgt | HTTPS FTP |
-Related structure data
Related structure data | 5lguC 5lhgC 5lhhC 5lhiC 2v1dS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | 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 |
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#2: Protein | 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 / |
#4: Chemical | ChemComp-6W3 / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 6.22 Å3/Da / Density % sol: 80 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion / pH: 6.5 Details: 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: 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. |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 1.00004 Å |
Detector | Type: MARRESEARCH / Detector: CCD / Date: Oct 15, 2013 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.00004 Å / Relative weight: 1 |
Reflection | Resolution: 3→57.75 Å / Num. obs: 50761 / % possible obs: 99.6 % / Observed criterion σ(F): 0 / Redundancy: 3.8 % / CC1/2: 0.992 / Rmerge(I) obs: 0.136 / Net I/σ(I): 9.2 |
Reflection shell | Resolution: 3→3.1 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.96 / Mean I/σ(I) obs: 1.1 / CC1/2: 0.382 / % possible all: 99.9 |
-Processing
Software |
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Refinement | Method to determine structure: FOURIER SYNTHESIS Starting model: 2V1D Resolution: 3→57.7 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.932 / SU B: 15.986 / SU ML: 0.255 / Cross valid method: THROUGHOUT / ESU R: 0.338 / ESU R Free: 0.253 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 85.793 Å2
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Refinement step | Cycle: 1 / Resolution: 3→57.7 Å
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