Structure of the Sensor Domain of Mycobacterium tuberculosis PknH Receptor Kinase Reveals a Conserved Binding Cleft

Cavazos, Alexandra; Prigozhin, Daniil M.; Alber, Tom

doi:10.1016/j.jmb.2012.06.011

Cited by 20 publications

(18 citation statements)

References 47 publications

(51 reference statements)

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“…A recent structural analysis, however, identified unusual features of the structure of this region. The crystal structure revealed the presence of two disulfide bonds that contribute rigidity to the structure and the presence of a deep cleft, the likely site of ligand binding, lined by a mix of hydrophobic and polar residues ( 70 ). The presumed ligand binding cleft is highly conserved among PknH orthologues and bears some similarity to binding sites of lipoproteins LprG and LppX.…”

Section: Pknhmentioning

confidence: 99%

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

2014

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The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The M. tuberculosis phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of M. tuberculosis biology, supporting a critical role for the STPKs in regulating M. tuberculosis physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into M. tuberculosis adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.

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Section: Pknhmentioning

confidence: 99%

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

2014

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“…109 Although the actual ligand for PknH remains at large, a crystal structure of the extracellular domain has revealed a large hydrophobic and polar cleft where cell wall related lipids could bind. 110 Future work will have to determine the precise inducer of PknH activation and the subsequent downstream effects on regulation of the crucial TCS-like transcription factor DosR.…”

Section: Mycobacterium Tuberculosismentioning

confidence: 99%

Regulation of transcription by eukaryotic-like serine-threonine kinases and phosphatases in Gram-positive bacterial pathogens

Wright

Ulijasz

2014

Virulence

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“…Due to the high homology of the PknB kinase domain with kinases from other Gram-positive bacteria, PknB constitutes a useful model to understand the enzymatic properties of STPKs. A lower level of structural information is available for the sensor extra-cellular domains of STPKs and most of the available structural information was achieved only recently [29-32]. This review will focus on recent structural findings of STPKs, specially focusing on those from human pathogens.…”

Section: Introductionmentioning

confidence: 99%

Bacterial Cell Division Regulation by Ser/Thr Kinases: A Structural Perspective

Ruggiero¹,

Simone²,

Smaldone³

et al. 2012

CPPS

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Recent genetic, biochemical and structural studies have established that eukaryotic-like Ser/Thr protein-kinases are critical mediators of developmental changes and host pathogen interactions in bacteria. Although with lower abundance compared to their homologues from eukaryotes, Ser/Thr protein-kinases are widespread in gram-positive bacteria. These data underline a key role of reversible Ser/Thr phosphorylation in bacterial physiology and virulence. Numerous studies have revealed how phosphorylation/dephosphorylation of Ser/Thr protein-kinases governs cell division and cell wall biosynthesis and that Ser/Thr protein kinases are responsible for distinct phenotypes, dependent on different environmental signals. In this review we discuss the current understandings of Ser/Thr protein-kinases functional processes based on structural data.

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Structure of the Sensor Domain of Mycobacterium tuberculosis PknH Receptor Kinase Reveals a Conserved Binding Cleft

Cited by 20 publications

References 47 publications

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

Mycobacterium tuberculosis Serine/Threonine Protein Kinases

Regulation of transcription by eukaryotic-like serine-threonine kinases and phosphatases in Gram-positive bacterial pathogens

Bacterial Cell Division Regulation by Ser/Thr Kinases: A Structural Perspective

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