4mao: Difference between revisions
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''' | ==RSK2 T493M C-Terminal Kinase Domain in Complex with RMM58== | ||
<StructureSection load='4mao' size='340' side='right' caption='[[4mao]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mao]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MAO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MAO FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28D:(2Z)-2-(1H-1,2,4-TRIAZOL-1-YL)-3-[3-(3,4,5-TRIMETHOXYPHENYL)-1H-INDAZOL-5-YL]PROP-2-ENENITRILE'>28D</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4m8t|4m8t]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=4mao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mao OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mao RCSB], [http://www.ebi.ac.uk/pdbsum/4mao PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles undergo beta-elimination at rates that span more than 3 orders of magnitude. These rates correlate inversely with the computed proton affinity of the corresponding carbanions, enabling the intrinsic reversibility of the thiol-Michael reaction to be tuned in a predictable manner. We apply these principles to the design of new reversible covalent kinase inhibitors with improved properties. A cocrystal structure of one such inhibitor reveals specific noncovalent interactions between the 1,2,4-triazole activating group and the kinase. Our experimental and computational study enables the design of new Michael acceptors, expanding the palette of reversible, cysteine-targeted electrophiles. | |||
Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis.,Krishnan S, Miller RM, Tian B, Mullins RD, Jacobson MP, Taunton J J Am Chem Soc. 2014 Sep 10;136(36):12624-30. doi: 10.1021/ja505194w. Epub 2014, Sep 2. PMID:25153195<ref>PMID:25153195</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Non-specific serine/threonine protein kinase]] | |||
[[Category: Miller, R M.]] | |||
[[Category: Taunton, J.]] | |||
[[Category: Covalent inhibitor]] | |||
[[Category: Phosphorylation]] | |||
[[Category: Protein kinase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 11:37, 22 October 2014
RSK2 T493M C-Terminal Kinase Domain in Complex with RMM58
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