Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23

Liu, Lijun; Thaker, Tarjani; Freed, Daniel M.; Frazier, Nicole Michael; Malhotra, Ketan; Lemmon, Mark A.; Jura, Natalia

doi:10.1016/j.str.2017.12.012

Cited by 6 publications

(8 citation statements)

References 35 publications

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“…In these complexes, the HER3 pseudokinase domain allosterically activates its partner HER kinase by stabilizing it in the active conformation through the formation of an asymmetric kinase dimer [30][31][32] . This allosteric functionality is encoded in all receptors in the EGFR family; HER3 has only this allosteric role and no catalytic role 33,34 .…”

Section: Her3mentioning

confidence: 99%

Prospects for pharmacological targeting of pseudokinases

Kung

Jura

2019

Nat Rev Drug Discov

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119

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Pseudokinases are members of the protein kinase superfamily but signal primarily through noncatalytic mechanisms. Many pseudokinases contribute to the pathologies of human diseases, yet they remain largely unexplored as drug targets owing to challenges associated with modulation of their biological functions. Our understanding of the structure and physiological roles of pseudokinases has improved substantially over the past decade, revealing intriguing similarities between pseudokinases and their catalytically active counterparts. Pseudokinases often adopt conformations that are analogous to those seen in catalytically active kinases and, in some cases, can also bind metal cations and/or nucleotides. Several clinically approved kinase inhibitors have been shown to influence the noncatalytic functions of active kinases, providing hope that similar properties in pseudokinases could be pharmacologically regulated. In this Review, we discuss known roles of pseudokinases in disease, their unique structural features and the progress that has been made towards developing pseudokinase-directed therapeutics.

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Section: Her3mentioning

confidence: 99%

Prospects for pharmacological targeting of pseudokinases

Kung

Jura

2019

Nat Rev Drug Discov

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119

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“…1A). We then compared the LET-23 homology model to the experimentally derived crystal structure of the LET-23 kinase domain (PDB: 5WNO 43 ; Supplementary Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

Knox

Joly

Linossi

et al. 2021

Sci Rep

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Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to the anthelmintics currently used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-selective manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-selective inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.

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“…To test the validity of a homology modeling approach, we first created a homology model of the C. elegans LET-23 kinase domain based on the solved structure of the orthologous human EGFR kinase domain (Protein Data Bank (PDB) structure 2ITX; [43]) (Supplementary Figure 1A). We then compared the LET-23 homology model to the experimentally derived crystal structure of the LET-23 kinase domain (PDB: 5WNO [44]; Supplementary Figure 1B).…”

Section: Three Kinases Are Candidate Targets For Anthelmintic Developmentioning

confidence: 99%

A Survey of the Kinome Pharmacopeia Reveals Multiple Scaffolds and Targets for the Development of Novel Anthelmintics

Knox

Zuercher

Roy³

2020

Preprint

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Over one billion people are currently infected with a parasitic nematode. Symptoms can include anemia, malnutrition, developmental delay, and in severe cases, death. Resistance is emerging to anthelmintic drugs used to treat nematode infection, prompting the need to develop new anthelmintics. Towards this end, we identified a set of kinases that may be targeted in a nematode-specific manner. We first screened 2040 inhibitors of vertebrate kinases for those that impair the model nematode Caenorhabditis elegans. By determining whether the terminal phenotype induced by each kinase inhibitor matched that of the predicted target mutant in C. elegans, we identified 17 druggable nematode kinase targets. Of these, we found that nematode EGFR, MEK1, and PLK1 kinases have diverged from vertebrates within their drug-binding pocket. For each of these targets, we identified small molecule scaffolds that may be further modified to develop nematode-specific inhibitors. Nematode EGFR, MEK1, and PLK1 therefore represent key targets for the development of new anthelmintic medicines.

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Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23

Cited by 6 publications

References 35 publications

Prospects for pharmacological targeting of pseudokinases

Prospects for pharmacological targeting of pseudokinases

A survey of the kinome pharmacopeia reveals multiple scaffolds and targets for the development of novel anthelmintics

A Survey of the Kinome Pharmacopeia Reveals Multiple Scaffolds and Targets for the Development of Novel Anthelmintics

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