2mt8: Difference between revisions
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New page: '''Unreleased structure''' The entry 2mt8 is ON HOLD Authors: Huang, Y., Wang, C., Craik, D. Description: Solution structure MTAbl13, a grafted MCoTI-II |
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The | ==Solution structure MTAbl13, a grafted MCoTI-II== | ||
<StructureSection load='2mt8' size='340' side='right'caption='[[2mt8]]' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2mt8]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MT8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MT8 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</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=2mt8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mt8 OCA], [https://pdbe.org/2mt8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mt8 RCSB], [https://www.ebi.ac.uk/pdbsum/2mt8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mt8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ITR2_MOMCO ITR2_MOMCO] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The constitutively active tyrosine kinase BCR-ABL is the underlying cause of chronic myeloid leukemia (CML). Current CML treatments rely on the long-term use of tyrosine kinase inhibitors (TKIs), which target the ATP binding site of BCR-ABL. Over the course of treatment, 20-30% of CML patients develop TKI resistance, which is commonly attributed to point mutations in the drug-binding region. We design a new class of peptide inhibitors that target the substrate-binding site of BCR-ABL by grafting sequences derived from abltide, the optimal substrate of Abl kinase, onto a cell-penetrating cyclotide MCoTI-II. Three grafted cyclotides show significant Abl kinase inhibition in vitro in the low micromolar range using a novel kinase inhibition assay. Our work also demonstrates that a reengineered MCoTI-II with abltide sequences grafted in both loop 1 and 6 inhibits the activity of [T315I]Abl in vitro, a mutant Abl kinase harboring the "gatekeeper" mutation which is notorious for being multidrug resistant. Results from serum stability and cell internalization studies confirm that the MCoTI-II scaffold provides enzymatic stability and cell-penetrating properties to the lead molecules. Taken together, our study highlights that reengineered cyclotides incorporating abltide-derived sequences are promising substrate-competitive inhibitors for Abl kinase and the T315I mutant. | |||
Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold.,Huang YH, Henriques ST, Wang CK, Thorstholm L, Daly NL, Kaas Q, Craik DJ Sci Rep. 2015 Aug 12;5:12974. doi: 10.1038/srep12974. PMID:26264857<ref>PMID:26264857</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2mt8" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Craik D]] | |||
[[Category: Huang Y]] | |||
[[Category: Wang C]] | |||
Latest revision as of 05:21, 17 October 2024
Solution structure MTAbl13, a grafted MCoTI-II
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