Abstract
With the advent of the sequencing programs of prokaryotic genomes, many examples of the presence of serine/threonine protein kinases in these organisms have been identified. Moreover, these kinases could be classified as homologues of those belonging to the well characterized superfamily of the eukaryotic serine/threonine and tyrosine kinases. Eleven such kinases were recognized in the genome of Mycobacterium tuberculosis. Here we report the crystal structure of an active form of PknB, one of the four M. tuberculosis kinases that are conserved in the downsized genome of Mycobacterium leprae and are therefore presumed to play an important role in the processes that regulate the complex life cycle of mycobacteria. Our structure confirms again the extraordinary conservation of the protein kinase fold and constitutes a landmark that extends this conservation across the evolutionary distance between high eukaryotes and eubacteria. The structure of PknB, in complex with a nucleotide triphosphate analog, reveals an enzyme in the active state with an unprecedented arrangement of the Gly-rich loop associated with a new conformation of the nucleotide gamma-phosphoryl group. It presents as well a partially disordered activation loop, suggesting an induced fit mode of binding for the so far unknown substrates of this kinase or for some modulating factor(s).
Highlights
The reversible phosphorylation of proteins constitutes one of the most widespread mechanisms involved in the regulation of different processes in living organisms
We report the crystal structure of an active form of PknB, one of the four M. tuberculosis kinases that are conserved in the downsized genome of Mycobacterium leprae and are presumed to play an important role in the processes that regulate the complex life cycle of mycobacteria
Overall Structure—The structure of the catalytic domain of M. tuberculosis PknB was solved by molecular replacement and refined at 2.2-Å resolution (Table II)
Summary
The reversible phosphorylation of proteins constitutes one of the most widespread mechanisms involved in the regulation of different processes in living organisms. Since several bacterial genes encoding STPKs, PTKs, or their counterpart phosphatases have been identified and cloned (for a review, see Ref. 5) Their existence raises the question of their role in signal transduction pathways, possibly involving complex networks equivalent to those widely studied in eukaryotes [6]. The pknA and pknB genes are found next to each other in a genomic region that is conserved in M. leprae and in other Actinomycetales like Streptomyces coelicolor This region includes one gene encoding a putative serine/threonine phosphatase and genes for proteins involved in the cell wall synthesis. What may be the role of these STPKs and phosphatases in the adaptation of mycobacteria to the intricate interactions that they maintain with their hosts remains an open question It would be of great interest to assess whether the two-component systems and the serine/threonine kinases and phosphatases may be interconnected in the regulation of certain functions
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