3svv: Difference between revisions
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[[ | ==Crystal Structure of T338C c-Src covalently bound to vinylsulfonamide-pyrazolopyrimidine 9== | ||
<StructureSection load='3svv' size='340' side='right' caption='[[3svv]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3svv]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3SVV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3SVV FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=VSP:N-(3-{[4-AMINO-1-(PROPAN-2-YL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-3-YL]METHYL}PHENYL)ETHANESULFONAMIDE'>VSP</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SRC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9031 Gallus gallus])</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=3svv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3svv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3svv RCSB], [http://www.ebi.ac.uk/pdbsum/3svv PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The conserved nature of the ATP-binding site of the > 500 human kinases renders the development of specific inhibitors a challenging task. A widely used chemical genetic strategy to overcome the specificity challenge exploits a large-to-small mutation of the gatekeeper residue (a conserved hydrophobic amino acid) and the use of a bulky inhibitor to achieve specificity via shape complementarity. However, in a number of cases, introduction of a glycine or alanine gatekeeper results in diminished kinase activity and ATP affinity. A new chemical genetic approach based on covalent complementarity between an engineered gatekeeper cysteine and an electrophilic inhibitor was developed to address these challenges. This strategy was evaluated with Src, a proto-oncogenic tyrosine kinase known to lose some enzymatic activity using the shape complementarity chemical genetic strategy. We found that Src with a cysteine gatekeeper recapitulates wild type activity and can be irreversibly inhibited both in vitro and in cells. A cocrystal structure of T338C c-Src with a vinylsulfonamide-derivatized pyrazolopyrimidine inhibitor was solved to elucidate the inhibitor binding mode. A panel of electrophilic inhibitors was analyzed against 307 kinases and MOK (MAPK/MAK/MRK overlapping kinase), one of only two human kinases known to have an endogenous cysteine gatekeeper. This analysis revealed remarkably few off-targets, making these compounds the most selective chemical genetic inhibitors reported to date. Protein engineering studies demonstrated that it is possible to increase inhibitor potency through secondary-site mutations. These results suggest that chemical genetic strategies based on covalent complementarity should be widely applicable to the study of protein kinases. | |||
Chemical genetic strategy for targeting protein kinases based on covalent complementarity.,Garske AL, Peters U, Cortesi AT, Perez JL, Shokat KM Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15046-52. Epub 2011 Aug 18. PMID:21852571<ref>PMID:21852571</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[ | *[[Tyrosine kinase|Tyrosine kinase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Gallus gallus]] | [[Category: Gallus gallus]] | ||
[[Category: Non-specific protein-tyrosine kinase]] | [[Category: Non-specific protein-tyrosine kinase]] | ||
[[Category: Cortesi, A | [[Category: Cortesi, A]] | ||
[[Category: Garske, A L | [[Category: Garske, A L]] | ||
[[Category: Perez, J | [[Category: Perez, J]] | ||
[[Category: Peters, U | [[Category: Peters, U]] | ||
[[Category: Shokat, K M | [[Category: Shokat, K M]] | ||
[[Category: Covalently bound ligand]] | [[Category: Covalently bound ligand]] | ||
[[Category: Cysteine gatekeeper]] | [[Category: Cysteine gatekeeper]] | ||
[[Category: Src]] | [[Category: Src]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 13:24, 9 December 2014
Crystal Structure of T338C c-Src covalently bound to vinylsulfonamide-pyrazolopyrimidine 9
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