4l18: Difference between revisions
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==Crystal structure of Runx1 and Ets1 bound to TCR alpha promoter (crystal form 3)== | |||
<StructureSection load='4l18' size='340' side='right' caption='[[4l18]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4l18]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L18 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L18 FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4l0y|4l0y]], [[4l0z|4l0z]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Runx1, Aml1, Cbfa2, Pebp2ab ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), ETS1, EWSR2 ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4l18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l18 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4l18 RCSB], [http://www.ebi.ac.uk/pdbsum/4l18 PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/RUNX1_MOUSE RUNX1_MOUSE]] Note=Mice with an Runx1 lacking the DNA-binding region are found to die between embryonic days 11.5 to 12.5 due to hemorrhaging in the central nervous system. This hemorrhaging is preceded by necrosis and hematopoiesis is blocked. | [[http://www.uniprot.org/uniprot/RUNX1_MOUSE RUNX1_MOUSE]] Note=Mice with an Runx1 lacking the DNA-binding region are found to die between embryonic days 11.5 to 12.5 due to hemorrhaging in the central nervous system. This hemorrhaging is preceded by necrosis and hematopoiesis is blocked. | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/RUNX1_MOUSE RUNX1_MOUSE]] CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL-3 and GM-CSF promoters. Essential for the development of normal hematopoiesis. Isoform 4 shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation (By similarity).<ref>PMID:8565077</ref> <ref>PMID:8622955</ref> [[http://www.uniprot.org/uniprot/ETS1_HUMAN ETS1_HUMAN]] Transcription factor.<ref>PMID:10698492</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Runx1 is required for definitive hematopoiesis and is well-known for its frequent chromosomal translocations and point mutations in leukemia. Runx1 regulates a variety of genes via Ets1 activation on an Ets1*Runx1 composite DNA sequence. The structural basis of such regulation remains unresolved. To address this problem, we determined the crystal structure of the ternary complex containing Runx11-242 and Ets1296-441 bound to T cell receptor alpha (TCRalpha) enhancer DNA. In the crystal, an Ets1-interacting domain of Runx1 is bound to the Ets1 DNA-binding domain and displaced an entire autoinhibitory module of Ets1, revealing a novel mechanism of Ets1 activation. The DNA binding and transcriptional studies with a variety of structure-guided Runx1 mutants confirmed a critical role of direct Ets1*Runx1 interaction in Ets1 activation. More importantly, the discovered mechanism provides a plausible explanation for how the Ets1*Runx1 interaction effectively activates not only a wild-type Ets1, but also a highly inhibited phosphorylated form of Ets1.Leukemia accepted article preview online, 20 March 2014; doi:10.1038/leu.2014.111. | |||
Structural basis of Ets1 activation by Runx1.,Shrivastava T, Mino K, Babayeva ND, Baranovskaya OI, Rizzino A, Tahirov TH Leukemia. 2014 Mar 20. doi: 10.1038/leu.2014.111. PMID:24646888<ref>PMID:24646888</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Ets1|Ets1]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Lk3 transgenic mice]] | |||
[[Category: Tahirov, T H.]] | [[Category: Tahirov, T H.]] | ||
[[Category: Ets domain]] | [[Category: Ets domain]] | ||
[[Category: Runt domain]] | [[Category: Runt domain]] | ||
[[Category: Transcription-dna complex]] | [[Category: Transcription-dna complex]] | ||
Revision as of 11:42, 22 October 2014
Crystal structure of Runx1 and Ets1 bound to TCR alpha promoter (crystal form 3)Crystal structure of Runx1 and Ets1 bound to TCR alpha promoter (crystal form 3)
Structural highlights
Disease[RUNX1_MOUSE] Note=Mice with an Runx1 lacking the DNA-binding region are found to die between embryonic days 11.5 to 12.5 due to hemorrhaging in the central nervous system. This hemorrhaging is preceded by necrosis and hematopoiesis is blocked. Function[RUNX1_MOUSE] CBF binds to the core site, 5'-PYGPYGGT-3', of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL-3 and GM-CSF promoters. Essential for the development of normal hematopoiesis. Isoform 4 shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation. Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter. Inhibits KAT6B-dependent transcriptional activation (By similarity).[1] [2] [ETS1_HUMAN] Transcription factor.[3] Publication Abstract from PubMedRunx1 is required for definitive hematopoiesis and is well-known for its frequent chromosomal translocations and point mutations in leukemia. Runx1 regulates a variety of genes via Ets1 activation on an Ets1*Runx1 composite DNA sequence. The structural basis of such regulation remains unresolved. To address this problem, we determined the crystal structure of the ternary complex containing Runx11-242 and Ets1296-441 bound to T cell receptor alpha (TCRalpha) enhancer DNA. In the crystal, an Ets1-interacting domain of Runx1 is bound to the Ets1 DNA-binding domain and displaced an entire autoinhibitory module of Ets1, revealing a novel mechanism of Ets1 activation. The DNA binding and transcriptional studies with a variety of structure-guided Runx1 mutants confirmed a critical role of direct Ets1*Runx1 interaction in Ets1 activation. More importantly, the discovered mechanism provides a plausible explanation for how the Ets1*Runx1 interaction effectively activates not only a wild-type Ets1, but also a highly inhibited phosphorylated form of Ets1.Leukemia accepted article preview online, 20 March 2014; doi:10.1038/leu.2014.111. Structural basis of Ets1 activation by Runx1.,Shrivastava T, Mino K, Babayeva ND, Baranovskaya OI, Rizzino A, Tahirov TH Leukemia. 2014 Mar 20. doi: 10.1038/leu.2014.111. PMID:24646888[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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