View source for 6kqp


==NSD1 SET domain in complex with SAM==
<StructureSection load='6kqp' size='340' side='right'caption='[[6kqp]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6kqp]] is a 1 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=6KQP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KQP 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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=6kqp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kqp OCA], [https://pdbe.org/6kqp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kqp RCSB], [https://www.ebi.ac.uk/pdbsum/6kqp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kqp ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NSD1_HUMAN NSD1_HUMAN] Sotos syndrome;Beckwith-Wiedemann syndrome due to NSD1 mutation;5q35 microduplication syndrome;Weaver syndrome. Sotos syndrome 1 (SOTOS1) [MIM:[https://omim.org/entry/117550 117550]: A childhood overgrowth syndrome characterized by pre- and postnatal overgrowth, developmental delay, mental retardation, advanced bone age, and abnormal craniofacial morphology including macrodolichocephaly with frontal bossing, frontoparietal sparseness of hair, apparent hypertelorism, downslanting palpebral fissures, and facial flushing. Common oral findings include: premature eruption of teeth; high, arched palate; pointed chin and, more rarely, prognathism. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:21196496</ref> <ref>PMID:11896389</ref> <ref>PMID:14997421</ref> <ref>PMID:12464997</ref> <ref>PMID:12807965</ref>   Weaver syndrome 1 (WVS1) [MIM:[https://omim.org/entry/277590 277590]: A syndrome of accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly. Distinguishing features of Weaver syndrome include broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nails. In addition, carpal bone development is advanced over the rest of the hand. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:12464997</ref> <ref>PMID:12807965</ref>   Beckwith-Wiedemann syndrome (BWS) [MIM:[https://omim.org/entry/130650 130650]: A disorder characterized by anterior abdominal wall defects including exomphalos (omphalocele), pre- and postnatal overgrowth, and macroglossia. Additional less frequent complications include specific developmental defects and a predisposition to embryonal tumors. Note=The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:14997421</ref>   Note=A chromosomal aberration involving NSD1 is found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NUP98.  Note=A chromosomal aberration involving NSD1 is found in an adult form of myelodysplastic syndrome (MDS). Insertion of NUP98 into NSD1 generates a NUP98-NSD1 fusion product.
== Function ==
[https://www.uniprot.org/uniprot/NSD1_HUMAN NSD1_HUMAN] Histone methyltransferase. Preferentially methylates 'Lys-36' of histone H3 and 'Lys-20' of histone H4 (in vitro). Transcriptional intermediary factor capable of both negatively or positively influencing transcription, depending on the cellular context.<ref>PMID:21196496</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development. Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain. The crystal structure of NSD1 in complex with covalently bound ligand reveals a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecules. Our covalent lead-compound BT5-demonstrates on-target activity in NUP98-NSD1 leukemia cells, including inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. This study will facilitate the development of the next generation of potent and selective inhibitors of the NSD histone methyltransferases.

Covalent inhibition of NSD1 histone methyltransferase.,Huang H, Howard CA, Zari S, Cho HJ, Shukla S, Li H, Ndoj J, Gonzalez-Alonso P, Nikolaidis C, Abbott J, Rogawski DS, Potopnyk MA, Kempinska K, Miao H, Purohit T, Henderson A, Mapp A, Sulis ML, Ferrando A, Grembecka J, Cierpicki T Nat Chem Biol. 2020 Aug 31. pii: 10.1038/s41589-020-0626-6. doi:, 10.1038/s41589-020-0626-6. PMID:32868895<ref>PMID:32868895</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6kqp" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cho HJ]]
[[Category: Cierpicki T]]