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

PABLO FERNANDEZ; A. WEHENKEL; M BELLINZONI; V CATHERINOT; N BARILONE; G LABESSE; M JACKSON; P ALZARI

FEBS LETTERS

ELSEVIER SCIENCE BV

Año: 2006 vol. 580 p. 3018 - 3022

0014-5793

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.