Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis

• DOI: 10.1073/pnas.0702842104
• Publication Date: 2007-07-07T00:41:41Z
• Authors: Nicole Scherr; Srinivas Honnappa; Gabriele Kunz; Philipp Mueller; Rajesh Jayachandran; Fritz Winkler; Jean Pieters; Michel O. Steinmetz
• Keywords: Protein kinase domain; Virulence factor; Mycobacterium smegmatis; c-Raf

The pathogenicity of mycobacteria such as Mycobacterium tuberculosis is closely associated with their capacity to survive within host macrophages. A crucial virulence factor for intracellular mycobacterial survival protein kinase G (PknG), a eukaryotic-like serine/threonine expressed by pathogenic that blocks the degradation in lysosomes. Inhibition PknG highly selective low-molecular-weight inhibitor AX20017 results transfer lysosomes and killing mycobacteria. Here, we report 2.4 Å x-ray crystal structure complex AX20017. unique multidomain topology reveals central domain flanked N- C-terminal rubredoxin tetratrico-peptide repeat domains, respectively. Directed mutagenesis suggests functions regulator activity. PknG-AX20017 further buried deep adenosine-binding site, targeting an active conformation domain. Remarkably, although reminiscent eukaryotic kinases, AX20017-binding pocket shaped set amino acid side chains are not found any human kinase. residues resulted drastic loss compound's inhibitory potency. Our explain specific mode action demonstrate factors homologous molecules can be successfully targeted block proliferation M. .