4csv: Difference between revisions
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''' | ==Tyrosine kinase AS - a common ancestor of Src and Abl bound to Gleevec== | ||
<StructureSection load='4csv' size='340' side='right' caption='[[4csv]], [[Resolution|resolution]] 2.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4csv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CSV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CSV FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</scene></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_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=4csv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4csv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4csv RCSB], [http://www.ebi.ac.uk/pdbsum/4csv PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve. | |||
Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism.,Wilson C, Agafonov RV, Hoemberger M, Kutter S, Zorba A, Halpin J, Buosi V, Otten R, Waterman D, Theobald DL, Kern D Science. 2015 Feb 20;347(6224):882-6. doi: 10.1126/science.aaa1823. PMID:25700521<ref>PMID:25700521</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Non-specific protein-tyrosine kinase]] | |||
[[Category: Agafonov, R V]] | |||
[[Category: Cruz, L]] | |||
[[Category: Hoemberger, M S]] | |||
[[Category: Kern, D]] | |||
[[Category: Kutter, S]] | [[Category: Kutter, S]] | ||
[[Category: Wilson, C]] | [[Category: Wilson, C]] | ||
[[Category: Zorba, A]] | [[Category: Zorba, A]] | ||
[[Category: | [[Category: Dfg]] | ||
[[Category: | [[Category: Transferase]] | ||
