View source for 4csv


==Tyrosine kinase AS - a common ancestor of Src and Abl bound to Gleevec==
<StructureSection load='4csv' size='340' side='right'caption='[[4csv]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4csv]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. 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 [https://proteopedia.org/fgij/fg.htm?mol=4CSV 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]] 2.05&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4csv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4csv OCA], [https://pdbe.org/4csv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4csv RCSB], [https://www.ebi.ac.uk/pdbsum/4csv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4csv ProSAT]</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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4csv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Agafonov RV]]
[[Category: Cruz L]]
[[Category: Hoemberger MS]]
[[Category: Kern D]]
[[Category: Kutter S]]
[[Category: Wilson C]]
[[Category: Zorba A]]