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The structure of PknB in complex with mitoxantrone, an ATP‐competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria
Author(s) -
Wehenkel Annemarie,
Fernandez Pablo,
Bellinzoni Marco,
Catherinot Vincent,
Barilone Nathalie,
Labesse Gilles,
Jackson Mary,
Alzari Pedro M.
Publication year - 2006
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2006.04.046
Subject(s) - chemistry , mitoxantrone , protein kinase a , kinase , cancer research , microbiology and biotechnology , biochemistry , biology , medicine , chemotherapy
Mycobacterium tuberculosis PknB is an essential receptor‐like protein kinase involved in cell growth control. Here, we demonstrate that mitoxantrone, an anthraquinone derivative used in cancer therapy, is a PknB inhibitor capable of preventing mycobacterial growth. The structure of the complex reveals that mitoxantrone partially occupies the adenine‐binding pocket in PknB, providing a framework for the design of compounds with potential therapeutic applications. PknB crystallizes as a ‘back‐to‐back’ homodimer identical to those observed in other structures of PknB in complex with ATP analogs. This organization resembles that of the RNA‐dependent protein kinase PKR, suggesting a mechanism for kinase activation in mycobacteria.