6kgr
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==LSD1-FCPA-MPE N5 adduct model== | |
| + | <StructureSection load='6kgr' size='340' side='right'caption='[[6kgr]], [[Resolution|resolution]] 2.32Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6kgr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6KGR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6KGR FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DJC:3-[4-[5-fluoranyl-2-(trifluoromethyl)phenyl]phenyl]propanal'>DJC</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6kgr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kgr OCA], [http://pdbe.org/6kgr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6kgr RCSB], [http://www.ebi.ac.uk/pdbsum/6kgr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6kgr ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/KDM1A_HUMAN KDM1A_HUMAN]] Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development.<ref>PMID:12032298</ref> <ref>PMID:15620353</ref> <ref>PMID:16079795</ref> <ref>PMID:17805299</ref> <ref>PMID:20228790</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Lysine-specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)-dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1-specific inhibitors have been pursued. Trans -2-phenylcyclopropylamine (2-PCPA)-based inhibitors featuring substitutions on the amino group have emerged, with submicromolar affinities toward LSD1 and high selectivities over monoamine oxidases (MAOs). We synthesized two N -alkylated 2-PCPA-based LSD1 inhibitors, S2116 and S2157, based on the previously developed S2101. S2116 and S2157 exhibited enhanced potency for LSD1 by 2.0- to 2.6-fold, as compared with S2101. In addition, they exhibited improved selectivity over MAOs. Structural analyses of LSD1 co-crystallized with S2101, S2116, S2157, or another N -alkylated inhibitor (FCPA-MPE) confirmed that the N -substituents enhance the potency of a 2-PCPA-based inhibitor of LSD1, without constituting the adduct formed with FAD. | ||
| - | + | Development and Structural Evaluation of N-alkylated Trans-2-phenylcyclopropylamine-based LSD1 Inhibitors.,Niwa H, Sato S, Handa N, Sengoku T, Umehara T, Yokoyama S ChemMedChem. 2020 Mar 12. doi: 10.1002/cmdc.202000014. PMID:32166890<ref>PMID:32166890</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6kgr" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Handa, N]] | ||
| + | [[Category: Niwa, H]] | ||
| + | [[Category: Sato, S]] | ||
| + | [[Category: Umehara, T]] | ||
| + | [[Category: Amine oxidase]] | ||
| + | [[Category: Chromatin]] | ||
| + | [[Category: Demethylase]] | ||
| + | [[Category: Fad]] | ||
| + | [[Category: Histone]] | ||
| + | [[Category: Mechanism-based inhibitor]] | ||
| + | [[Category: Oxidoreductase]] | ||
Revision as of 10:05, 27 March 2020
LSD1-FCPA-MPE N5 adduct model
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Categories: Large Structures | Handa, N | Niwa, H | Sato, S | Umehara, T | Amine oxidase | Chromatin | Demethylase | Fad | Histone | Mechanism-based inhibitor | Oxidoreductase
