View source for 5lhg


==Structure 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==
<StructureSection load='5lhg' size='340' side='right'caption='[[5lhg]], [[Resolution|resolution]] 3.34&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lhg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LHG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LHG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.34&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6X3:4-METHYL-N-[4-[[4-[(1-METHYL-4-PIPERIDYL)OXY]PHENOXY]METHYL]PHENYL]THIENO[3,2-B]PYRROLE-5-CARBOXAMIDE'>6X3</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5lhg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lhg OCA], [https://pdbe.org/5lhg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lhg RCSB], [https://www.ebi.ac.uk/pdbsum/5lhg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lhg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RCOR1_HUMAN RCOR1_HUMAN] Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. 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 and controls hematopoietic differentiation.<ref>PMID:11516394</ref> <ref>PMID:11171972</ref> <ref>PMID:12032298</ref> <ref>PMID:12399542</ref> <ref>PMID:12493763</ref> <ref>PMID:16140033</ref> <ref>PMID:16079794</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

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.,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 OA, Dessanti P, Minucci S, Vultaggio S, Zagarri E, Varasi M, Mercurio C J Med Chem. 2017 Feb 27. doi: 10.1021/acs.jmedchem.6b01019. PMID:28186757<ref>PMID:28186757</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lhg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cecatiello V]]
[[Category: Pasqualato S]]