6u9m: Difference between revisions
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==MLL1 SET N3861I/Q3867L bound to inhibitor 16 (TC-5109)== | ==MLL1 SET N3861I/Q3867L bound to inhibitor 16 (TC-5109)== | ||
<StructureSection load='6u9m' size='340' side='right'caption='[[6u9m]]' scene=''> | <StructureSection load='6u9m' size='340' side='right'caption='[[6u9m]], [[Resolution|resolution]] 2.05Å' 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=6U9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U9M FirstGlance]. <br> | <table><tr><td colspan='2'>[[6u9m]] 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=6U9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U9M 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=6u9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u9m OCA], [https://pdbe.org/6u9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u9m RCSB], [https://www.ebi.ac.uk/pdbsum/6u9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u9m ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.05Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=Q2M:5-{[(3S)-3-amino-3-carboxypropyl]({1-[(thiophen-2-yl)methyl]azetidin-3-yl}methyl)amino}-5-deoxyadenosine'>Q2M</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6u9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u9m OCA], [https://pdbe.org/6u9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u9m RCSB], [https://www.ebi.ac.uk/pdbsum/6u9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u9m ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/KMT2A_HUMAN KMT2A_HUMAN] Acute myeloid leukemia with 11q23 abnormalities;Precursor B-cell acute lymphoblastic leukemia;Wiedemann-Steiner syndrome;Acute biphenotypic leukemia;Acute undifferentiated leukemia;Bilineal acute leukemia. The disease is caused by mutations affecting the gene represented in this entry. Chromosomal aberrations involving KMT2A are a cause of acute leukemias. Translocation t(1;11)(q21;q23) with MLLT11/AF1Q; translocation t(3;11)(p21;q23) with NCKIPSD/AF3p21; translocation t(3,11)(q25,q23) with GMPS; translocation t(4;11)(q21;q23) with AFF1/MLLT2/AF4; insertion ins(5;11)(q31;q13q23) with AFF4/AF5Q31; translocation t(5;11)(q12;q23) with AF5-alpha/CENPK; translocation t(6;11)(q27;q23) with MLLT4/AF6; translocation t(9;11)(p22;q23) with MLLT3/AF9; translocation t(10;11)(p11.2;q23) with ABI1; translocation t(10;11)(p12;q23) with MLLT10/AF10; t(11;15)(q23;q14) with CASC5 and ZFYVE19; translocation t(11;17)(q23;q21) with MLLT6/AF17; translocation t(11;19)(q23;p13.3) with ELL; translocation t(11;19)(q23;p13.3) with MLLT1/ENL; translocation t(11;19)(q23;p23) with GAS7; translocation t(X;11)(q13;q23) with FOXO4/AFX1. Translocation t(3;11)(q28;q23) with LPP. Translocation t(10;11)(q22;q23) with TET1. Translocation t(9;11)(q34;q23) with DAB2IP. Translocation t(4;11)(p12;q23) with FRYL. Fusion proteins KMT2A-MLLT1, KMT2A-MLLT3 and KMT2A-ELL interact with PPP1R15A and, on the contrary to unfused KMT2A, inhibit PPP1R15A-induced apoptosis. A chromosomal aberration involving KMT2A may be a cause of chronic neutrophilic leukemia. Translocation t(4;11)(q21;q23) with SEPT11. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/KMT2A_HUMAN KMT2A_HUMAN] Histone methyltransferase that plays an essential role in early development and hematopoiesis. Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac). In the MLL1/MLL complex, it specifically mediates H3K4me, a specific tag for epigenetic transcriptional activation. Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity. Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9'. Required for transcriptional activation of HOXA9. Promotes PPP1R15A-induced apoptosis.<ref>PMID:10490642</ref> <ref>PMID:12453419</ref> <ref>PMID:15960975</ref> <ref>PMID:19556245</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The mixed-lineage leukemia (MLL) protein, also known as MLL1, is a lysine methyltransferase specifically responsible for methylation of histone 3 lysine 4. MLL has been pursued as an attractive therapeutic target for the treatment of acute leukemia carrying the MLL fusion gene or MLL leukemia. Herein, we report the design, synthesis, and evaluation of an S-adenosylmethionine-based focused chemical library which led to the discovery of potent small-molecule inhibitors directly targeting the MLL SET domain. Determination of cocrystal structures for a number of these MLL inhibitors reveals that they adopt a unique binding mode that locks the MLL SET domain in an open, inactive conformation. | |||
Discovery of Potent Small-Molecule Inhibitors of MLL Methyltransferase.,Chern TR, Liu L, Petrunak E, Stuckey JA, Wang M, Bernard D, Zhou H, Lee S, Dou Y, Wang S ACS Med Chem Lett. 2020 May 14;11(6):1348-1352. doi:, 10.1021/acsmedchemlett.0c00229. eCollection 2020 Jun 11. PMID:32551023<ref>PMID:32551023</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6u9m" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | *[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Petrunak EM]] | [[Category: Petrunak EM]] | ||
[[Category: Stuckey JA]] | [[Category: Stuckey JA]] | ||