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| ==Solution structure MTAbl13, a grafted MCoTI-II== | | ==Solution structure MTAbl13, a grafted MCoTI-II== |
- | <StructureSection load='2mt8' size='340' side='right'caption='[[2mt8]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='2mt8' size='340' side='right'caption='[[2mt8]]' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[2mt8]] is a 1 chain structure. 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 [http://proteopedia.org/fgij/fg.htm?mol=2MT8 FirstGlance]. <br> | + | <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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2mt8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mt8 OCA], [http://pdbe.org/2mt8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mt8 RCSB], [http://www.ebi.ac.uk/pdbsum/2mt8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2mt8 ProSAT]</span></td></tr> | + | </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> | | </table> |
| + | == Function == |
| + | [https://www.uniprot.org/uniprot/ITR2_MOMCO ITR2_MOMCO] |
| <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
- | [[Category: Craik, D]] | + | [[Category: Synthetic construct]] |
- | [[Category: Huang, Y]] | + | [[Category: Craik D]] |
- | [[Category: Wang, C]] | + | [[Category: Huang Y]] |
- | [[Category: Cyclotide]] | + | [[Category: Wang C]] |
- | [[Category: Hydrolase inhibitor]]
| + | |
- | [[Category: Trypsin inhibitor]]
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| Structural highlights
Function
ITR2_MOMCO
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Huang YH, Henriques ST, Wang CK, Thorstholm L, Daly NL, Kaas Q, Craik DJ. Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold. Sci Rep. 2015 Aug 12;5:12974. doi: 10.1038/srep12974. PMID:26264857 doi:http://dx.doi.org/10.1038/srep12974
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