The crystal structure of the catalytic domain of the ser/thr kinase PknA from <i>M. tuberculosis</i>
 shows an Src-like autoinhibited conformation

Wagner, T.; Alexandre, M.; Durán, Rosario; Barilone, Nathalie; Wehenkel, Annemarie; Alzari, Pedro M.; Bellinzoni, M.

doi:10.1002/prot.24754

Cited by 11 publications

(8 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early work showed that PknA and PknB can cross-phosphorylate each other [8], though later data suggested unidirectional trans-phosphorylation of PknA by PknB, leading to the hypothesis that PknB regulates PknA activity [47]. Subsequent work, however, showed that PknA autophosphorylates in the mycobacterial cell and that PknA abundance is unaltered when PknB is depleted [15,48]. Our data showing limited overlap in peptides that are differentially phosphorylated in the pknA versus pknB depletion strains argue against a pathway in which PknB activates PknA.…”

Section: Plos Pathogensmentioning

confidence: 99%

Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility

et al. 2020

View full text Add to dashboard Cite

The Mycobacterium tuberculosis Ser/Thr protein kinases PknA and PknB are essential for growth and have been proposed as possible drug targets. We used a titratable conditional depletion system to investigate the functions of these kinases. Depletion of PknA or PknB or both kinases resulted in growth arrest, shortening of cells, and time-dependent loss of acidfast staining with a concomitant decrease in mycolate synthesis and accumulation of trehalose monomycolate. Depletion of PknA and/or PknB resulted in markedly increased susceptibility to β-lactam antibiotics, and to the key tuberculosis drug rifampin. Phosphoproteomic analysis showed extensive changes in protein phosphorylation in response to PknA depletion and comparatively fewer changes with PknB depletion. These results identify candidate substrates of each kinase and suggest specific and coordinate roles for PknA and PknB in regulating multiple essential physiologies. These findings support these kinases as targets for new antituberculosis drugs and provide a valuable resource for targeted investigation of mechanisms by which protein phosphorylation regulates pathways required for growth and virulence in M. tuberculosis.

show abstract

Section: Plos Pathogensmentioning

confidence: 99%

Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Hence, the precise cues associated with the activation of PknA and its regulation is yet to be deciphered. The crystal structure of PknA revealed that in the absence of a bound substrate or ATP, PknA is present in an auto‐inhibited state . The availability of crystal structure is an invaluable tool for the design of design novel inhibitors that would specifically target PknA.…”

Section: Introductionmentioning

confidence: 99%

Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development

2018

View full text Add to dashboard Cite

The emergence of increasingly drug-resistant Mycobacterium tuberculosis strains has become a crucial public health concern. In order to effectively treat tuberculosis, it is imperative to find newer drug targets, which are important for the in vivo bacterial survival and persistence. Phosphorylation based signaling cascades modulated by eukaryotic-like serine/threonine protein kinases and phosphatase in M. tuberculosis, transduce extracellular stimuli to a cellular response ensuing pathogen's growth, persistence and pathogenesis. Of the 11 STPKs that M. tuberculosis genome encodes, three kinases, namely PknA, PknB and PknG and the sole serine/threonine phosphatase PstP are crucial for the intracellular survival of the bacteria. PknA and PknB regulates cell growth, cell wall synthesis and morphological changes during bacterial cell division; while PknG modulates metabolic changes in response to stress and aids in bacterial survival during latency like conditions. PstP functions to dephosphorylate STPKs and their substrates and hence is important at nearly all stages of infection. Here, we review the current knowledge on PstP, PknA, PknB and PknG based on the genetic, biochemical, and functional studies in M. tuberculosis physiopathology. We further explore the potential of these molecules as targets for therapeutic intervention and discuss the advancement made in the development of inhibitors against these targets. © 2018 IUBMB Life, 70(9):889-904, 2018.

show abstract

“…Further, the salt bridge between the catalytic residue Lys41 and Glu60 in helix αC, one of the hallmarks of an ePK active state , is hindered in PknI by the side chain of Ile162 in the activation segment (Fig. A), similarly to the Src‐like autoinhibited conformation observed in another M. tuberculosis Ser/Thr kinase, PknA . Thus, the side chains of residues Lys41 and Glu60 are ca.…”

Section: Resultsmentioning

confidence: 92%

The crystal structure of PknI from Mycobacterium tuberculosis shows an inactive, pseudokinase‐like conformation

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

The crystal structure of the catalytic domain of the ser/thr kinase PknA from M. tuberculosis shows an Src-like autoinhibited conformation

Cited by 11 publications

References 20 publications

Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility

Protein kinases PknA and PknB independently and coordinately regulate essential Mycobacterium tuberculosis physiologies and antimicrobial susceptibility

Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development

The crystal structure of PknI from Mycobacterium tuberculosis shows an inactive, pseudokinase‐like conformation

Contact Info

Product

Resources

About