The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria.

Annemarie Wehenkel (1) , Pablo Fernandez (1) , Marco Bellinzoni (1) , Vincent Catherinot (2) , Nathalie Barilone (3) , Gilles Labesse (2) , Mary Jackson (3) , Pedro M. Alzari (1)

1 Biochimie Structurale
2 CBS - Centre de Biochimie Structurale [Montpellier]
3 Génétique mycobactérienne - Mycobacterial genetics

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.

Mots clés: Drug design; Back-to-back dimerization; Crystal structure; Ser/Thr protein kinase-inhibitor complex; Mycobacterium tuberculosis

Domaines: Cristallographie; Biologie structurale [q-bio.BM]; Biochimie, Biologie Moléculaire; Bio-informatique [q-bio.QM]; Biophysique [physics.bio-ph]; Biologie cellulaire

Annemarie Wehenkel, Pablo Fernandez, Marco Bellinzoni, Vincent Catherinot, Nathalie Barilone, et al.. The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria.. FEBS Letters, 2006, 580 (13), pp.3018-22. ⟨10.1016/j.febslet.2006.04.046⟩. ⟨pasteur-03144516⟩