2MT8

Solution structure MTAbl13, a grafted MCoTI-II

Summary for 2MT8

• Entry DOI: 10.2210/pdb2mt8/pdb
• NMR Information: BMRB: 25152
• Descriptor: MTAbl13 of grafted MCoTI-II (1 entity in total)
• Functional Keywords: cyclotide, trypsin inhibitor, hydrolase inhibitor
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 4148.75

Authors

Huang, Y.,Wang, C.,Craik, D. (deposition date: 2014-08-15, release date: 2015-10-14, Last modification date: 2024-10-16)

Primary citation

Huang, Y.H.,Henriques, S.T.,Wang, C.K.,Thorstholm, L.,Daly, N.L.,Kaas, Q.,Craik, D.J.
Design of substrate-based BCR-ABL kinase inhibitors using the cyclotide scaffold.
Sci Rep, 5:12974-12974, 2015

PubMed Abstract: 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.

PubMed: 26264857
DOI: 10.1038/srep12974

Experimental method

SOLUTION NMR