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Slowly on, Slowly off: Bisubstrate‐Analogue Conjugates of 5‐Iodotubercidin and Histone H3 Peptide Targeting Protein Kinase Haspin
Author(s) -
Kestav Katrin,
Viht Kaido,
Konovalov Anton,
Enkvist Erki,
Uri Asko,
Lavogina Darja
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600697
Subject(s) - histone h3 , adenosine kinase , kinase , biochemistry , histone , protein kinase a , phosphorylation , peptide , chemistry , cyclin dependent kinase 1 , biology , microbiology and biotechnology , adenosine , dna , cell cycle , cell , adenosine deaminase
The atypical protein kinase haspin is a key player in mitosis by catalysing the phosphorylation of Thr3 in histone H3, and thus ensuring the normal function of the chromosomal passenger complex. Here, we report the development of bisubstrate‐analogue inhibitors targeting haspin. The compounds were constructed by linking 5‐iodotubercidin to the N terminus of histone H3 peptide. The new conjugates show high affinity (sub‐nanomolar K D ) towards haspin as well as slow kinetics of association and dissociation (residence time of several hours). This reflects a unique binding mode and translated into improved selectivity. The latter was confirmed in a biochemical binding/displacement assay with a panel of ten protein kinases, in a thermal shift assay with off‐targets of 5‐iodotubercidin (adenosine kinase and the Cdc2‐like kinase family) and in assay with spiked HeLa cell lysate.