3mk8: Difference between revisions
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[[Image: | ==The MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis Sensitizer== | ||
<StructureSection load='3mk8' size='340' side='right' caption='[[3mk8]], [[Resolution|resolution]] 2.32Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mk8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MK8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MK8 FirstGlance]. <br> | |||
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MK8:2-METHYL-L-NORLEUCINE'>MK8</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2L3, MCL-1, MCL1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3mk8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mk8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mk8 RCSB], [http://www.ebi.ac.uk/pdbsum/3mk8 PDBsum]</span></td></tr> | |||
</table> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/mk/3mk8_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition. | |||
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.,Stewart ML, Fire E, Keating AE, Walensky LD Nat Chem Biol. 2010 Aug;6(8):595-601. Epub 2010 Jun 20. PMID:20562877<ref>PMID:20562877</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Bcl-2|Bcl-2]] | *[[Bcl-2|Bcl-2]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Fire, E | [[Category: Fire, E]] | ||
[[Category: Keating, A E | [[Category: Keating, A E]] | ||
[[Category: Stewart, M | [[Category: Stewart, M]] | ||
[[Category: Walensky, L D | [[Category: Walensky, L D]] | ||
[[Category: Anti-apoptotic]] | [[Category: Anti-apoptotic]] | ||
[[Category: Apoptosis]] | [[Category: Apoptosis]] | ||
Revision as of 09:05, 9 December 2014
The MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis Sensitizer
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