6wzw: Difference between revisions
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==Ash1L SET domain in complex with AS-85== | ==Ash1L SET domain in complex with AS-85== | ||
<StructureSection load='6wzw' size='340' side='right'caption='[[6wzw]]' scene=''> | <StructureSection load='6wzw' size='340' side='right'caption='[[6wzw]], [[Resolution|resolution]] 1.69Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WZW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WZW FirstGlance]. <br> | <table><tr><td colspan='2'>[[6wzw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WZW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WZW FirstGlance]. <br> | ||
</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=6wzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wzw OCA], [https://pdbe.org/6wzw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wzw RCSB], [https://www.ebi.ac.uk/pdbsum/6wzw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wzw ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UG7:N-{[3-(3-carbamothioylphenyl)-1-{1-[(trifluoromethyl)sulfonyl]piperidin-4-yl}-1H-indol-6-yl]methyl}azetidine-3-carboxamide'>UG7</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ASH1L, KIAA1420, KMT2H ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6wzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wzw OCA], [https://pdbe.org/6wzw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wzw RCSB], [https://www.ebi.ac.uk/pdbsum/6wzw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wzw ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/ASH1L_HUMAN ASH1L_HUMAN]] Histone methyltransferase specifically methylating 'Lys-36' of histone H3 (H3K36me).<ref>PMID:21239497</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents. | |||
Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.,Rogawski DS, Deng J, Li H, Miao H, Borkin D, Purohit T, Song J, Chase J, Li S, Ndoj J, Klossowski S, Kim E, Mao F, Zhou B, Ropa J, Krotoska MZ, Jin Z, Ernst P, Feng X, Huang G, Nishioka K, Kelly S, He M, Wen B, Sun D, Muntean A, Dou Y, Maillard I, Cierpicki T, Grembecka J Nat Commun. 2021 May 14;12(1):2792. doi: 10.1038/s41467-021-23152-6. PMID:33990599<ref>PMID:33990599</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6wzw" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Cierpicki T]] | [[Category: Cierpicki, T]] | ||
[[Category: Deng J]] | [[Category: Deng, J]] | ||
[[Category: Grembecka J]] | [[Category: Grembecka, J]] | ||
[[Category: Li H]] | [[Category: Li, H]] | ||
[[Category: Complex]] | |||
[[Category: Methyltransferase]] | |||
[[Category: Protein binding]] | |||
[[Category: Transferase-inhibitor complex]] | |||
Revision as of 12:24, 26 May 2021
Ash1L SET domain in complex with AS-85Ash1L SET domain in complex with AS-85
Structural highlights
Function[ASH1L_HUMAN] Histone methyltransferase specifically methylating 'Lys-36' of histone H3 (H3K36me).[1] Publication Abstract from PubMedASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents. Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.,Rogawski DS, Deng J, Li H, Miao H, Borkin D, Purohit T, Song J, Chase J, Li S, Ndoj J, Klossowski S, Kim E, Mao F, Zhou B, Ropa J, Krotoska MZ, Jin Z, Ernst P, Feng X, Huang G, Nishioka K, Kelly S, He M, Wen B, Sun D, Muntean A, Dou Y, Maillard I, Cierpicki T, Grembecka J Nat Commun. 2021 May 14;12(1):2792. doi: 10.1038/s41467-021-23152-6. PMID:33990599[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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