5lt7: Difference between revisions
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==Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives== | ==Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives== | ||
<StructureSection load='5lt7' size='340' side='right' caption='[[5lt7]], [[Resolution|resolution]] 1.51Å' scene=''> | <StructureSection load='5lt7' size='340' side='right'caption='[[5lt7]], [[Resolution|resolution]] 1.51Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5lt7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LT7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[5lt7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LT7 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=76L:(2~{ | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=76L:[(2~{S},5~{R})-1-[(2~{R},3~{S},4~{R},5~{R})-5-(6-AMINOPURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]-5-AZANIUMYL-6-OXIDANYL-6-OXIDANYLIDENE-HEXAN-2-YL]-[(2~{R})-2-OXIDANYLPROPYL]AZANIUM'>76L</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</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">SETD2, HIF1, HYPB, KIAA1732, KMT3A, SET2, HSPC069 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></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=5lt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lt7 OCA], [http://pdbe.org/5lt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lt7 RCSB], [http://www.ebi.ac.uk/pdbsum/5lt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lt7 ProSAT]</span></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=5lt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lt7 OCA], [http://pdbe.org/5lt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lt7 RCSB], [http://www.ebi.ac.uk/pdbsum/5lt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lt7 ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 5lt7" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5lt7" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Histone-lysine N-methyltransferase]] | [[Category: Histone-lysine N-methyltransferase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Heightman, T]] | [[Category: Heightman, T]] | ||
[[Category: Pathuri, P]] | [[Category: Pathuri, P]] | ||
Revision as of 09:30, 16 October 2019
Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin DerivativesStructure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives
Structural highlights
Function[SETD2_HUMAN] Histone methyltransferase that methylates 'Lys-36' of histone H3. H3 'Lys-36' methylation represents a specific tag for epigenetic transcriptional activation. Probably plays a role in chromatin structure modulation during elongation via its interaction with hyperphosphorylated POLR2A. Binds DNA at promoters. May also act as a transcription activator that binds to promoters. Binds to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.[1] Publication Abstract from PubMedThe members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 A resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET. Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.,Tisi D, Chiarparin E, Tamanini E, Pathuri P, Coyle JE, Hold A, Holding FP, Amin N, Martin AC, Rich SJ, Berdini V, Yon J, Acklam P, Burke R, Drouin L, Harmer JE, Jeganathan F, van Montfort RL, Newbatt Y, Tortorici M, Westlake M, Wood A, Hoelder S, Heightman TD ACS Chem Biol. 2016 Sep 27. PMID:27571355[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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