View source for 5lt7


==Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives==
<StructureSection load='5lt7' size='340' side='right' caption='[[5lt7]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
== 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>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=76L:(2~{R},5~{S})-6-[(2~{R},3~{S},4~{R},5~{R})-5-(6-AMINOPURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]-2-AZANYL-5-[[(2~{R})-2-OXIDANYLPROPYL]AMINO]HEXANOIC+ACID'>76L</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/SETD2_HUMAN 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.<ref>PMID:16118227</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The 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<ref>PMID:27571355</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lt7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Histone-lysine N-methyltransferase]]
[[Category: Heightman, T]]
[[Category: Pathuri, P]]
[[Category: Tisi, D]]
[[Category: Lysine methyltransferase setd2 set domain]]
[[Category: Transferase]]