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Journal of Medicinal Chemistry Jan 2022Allosteric kinase inhibitors are thought to have high selectivity and are prime candidates for kinase drug discovery. In addition, the exploration of allosteric... (Review)
Review
Allosteric kinase inhibitors are thought to have high selectivity and are prime candidates for kinase drug discovery. In addition, the exploration of allosteric mechanisms represents an attractive topic for basic research and drug design. Although the identification and characterization of allosteric kinase inhibitors is still far from being routine, X-ray structures of kinase complexes have been determined for a significant number of such inhibitors. On the basis of structural data, allosteric inhibitors can be confirmed. We report a comprehensive survey of allosteric kinase inhibitors and activators from publicly available X-ray structures, map their binding sites, and determine their distribution over binding pockets in kinases. In addition, we discuss structural features of these compounds and identify active structural analogues and high-confidence target annotations, indicating additional activities for a subset of allosteric inhibitors. This contribution aims to provide a detailed structure-based view of allosteric kinase inhibition.
Topics: Allosteric Regulation; Animals; Drug Design; Drug Discovery; Humans; Models, Molecular; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship
PubMed: 33476146
DOI: 10.1021/acs.jmedchem.0c02076 -
Future Medicinal Chemistry Aug 2020
Topics: Drug Discovery; Humans; Ligands; Protein Kinase Inhibitors; Protein Kinases
PubMed: 32597212
DOI: 10.4155/fmc-2020-0118 -
Genes Jun 2020In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in... (Review)
Review
In quiescent cells, primary cilia function as a mechanosensor that converts mechanic signals into chemical activities. This unique organelle plays a critical role in restricting mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is essential for quiescent cells to maintain their quiescence. Multiple mechanisms have been identified that mediate the inhibitory effect of primary cilia on mTORC1 signaling. These mechanisms depend on several tumor suppressor proteins localized within the ciliary compartment, including liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), polycystin-1, and polycystin-2. Conversely, changes in mTORC1 activity are able to affect ciliogenesis and stability indirectly through autophagy. In this review, we summarize recent advances in our understanding of the reciprocal regulation of mTORC1 and primary cilia.
Topics: AMP-Activated Protein Kinase Kinases; Autophagy; Cilia; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanotransduction, Cellular; Protein Kinases; Protein Serine-Threonine Kinases; Signal Transduction; TRPP Cation Channels
PubMed: 32604881
DOI: 10.3390/genes11060711 -
Current Opinion in Chemical Biology Apr 2023Mass spectrometry-based phosphoproteomics is currently the leading methodology for the study of global kinase signaling. The scientific community is continuously... (Review)
Review
Mass spectrometry-based phosphoproteomics is currently the leading methodology for the study of global kinase signaling. The scientific community is continuously releasing technological improvements for sensitive and fast identification of phosphopeptides, and their accurate quantification. To interpret large-scale phosphoproteomics data, numerous bioinformatic resources are available that help understanding kinase network functional role in biological systems upon perturbation. Some of these resources are databases of phosphorylation sites, protein kinases and phosphatases; others are bioinformatic algorithms to infer kinase activity, predict phosphosite functional relevance and visualize kinase signaling networks. In this review, we present the latest experimental and bioinformatic tools to profile protein kinase signaling networks and provide examples of their application in biomedicine.
Topics: Proteomics; Phosphorylation; Protein Kinases; Signal Transduction; Mass Spectrometry; Phosphoproteins
PubMed: 36657259
DOI: 10.1016/j.cbpa.2022.102260 -
Molecules (Basel, Switzerland) Apr 2023Protein phosphorylation is a ubiquitous post-translational modification controlled by the opposing activities of protein kinases and phosphatases, which regulate diverse... (Review)
Review
Protein phosphorylation is a ubiquitous post-translational modification controlled by the opposing activities of protein kinases and phosphatases, which regulate diverse biological processes in all kingdoms of life. One of the key challenges to a complete understanding of phosphoregulatory networks is the unambiguous identification of kinase and phosphatase substrates. Liquid chromatography-coupled mass spectrometry (LC-MS/MS) and associated phosphoproteomic tools enable global surveys of phosphoproteome changes in response to signaling events or perturbation of phosphoregulatory network components. Despite the power of LC-MS/MS, it is still challenging to directly link kinases and phosphatases to specific substrate phosphorylation sites in many experiments. Here, we survey common LC-MS/MS-based phosphoproteomic workflows for identifying protein kinase and phosphatase substrates, noting key advantages and limitations of each. We conclude by discussing the value of inducible degradation technologies coupled with phosphoproteomics as a new approach that overcomes some limitations of current methods for substrate identification of kinases, phosphatases, and other regulatory enzymes.
Topics: Phosphoric Monoester Hydrolases; Chromatography, Liquid; Tandem Mass Spectrometry; Phosphorylation; Protein Kinases; Phosphoproteins
PubMed: 37175085
DOI: 10.3390/molecules28093675 -
Marine Drugs Sep 2019Autophagy is a lysosomal pathway that degrades and recycles unused or dysfunctional cell components as well as toxic cytosolic materials. Basal autophagy favors cell... (Review)
Review
Autophagy is a lysosomal pathway that degrades and recycles unused or dysfunctional cell components as well as toxic cytosolic materials. Basal autophagy favors cell survival. However, the aberrant regulation of autophagy can promote pathological conditions. The autophagy pathway is regulated by several cell-stress and cell-survival signaling pathways that can be targeted for the purpose of disease control. In experimental models of disease, the carotenoid astaxanthin has been shown to modulate autophagy by regulating signaling pathways, including the AMP-activated protein kinase (AMPK), cellular homolog of murine thymoma virus akt8 oncogene (Akt), and mitogen-activated protein kinase (MAPK), such as c-Jun N-terminal kinase (JNK) and p38. Astaxanthin is a promising therapeutic agent for the treatment of a wide variety of diseases by regulating autophagy.
Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Signal Transduction; Xanthophylls; p38 Mitogen-Activated Protein Kinases
PubMed: 31547619
DOI: 10.3390/md17100546 -
Plant Signaling & Behavior Dec 2023Hypoxia triggers reactive oxygen species (ROS)-induced elevation in cytoplasmic calcium (Ca) in the plant cells. Calcium-dependent protein kinase 12 (CPK12) acts as a...
Hypoxia triggers reactive oxygen species (ROS)-induced elevation in cytoplasmic calcium (Ca) in the plant cells. Calcium-dependent protein kinase 12 (CPK12) acts as a sensor to recognize the Ca signature and is activated by autophosphorylation. Then, the CPK12 moves into the nucleus with the help of phosphatidic acid (PA) and phosphorylates ERF-VII family proteins that activate hypoxia signaling and response. The study provides a novel mechanism of hypoxia signaling in plants. Moreover, the mechanism of hypoxia-specific Ca signature generation remains elusive.
Topics: Protein Kinases; Hypoxia; Cell Hypoxia; Phosphorylation; Calcium; Reactive Oxygen Species
PubMed: 37875477
DOI: 10.1080/15592324.2023.2273593 -
Bioconjugate Chemistry Jan 2023Protein kinase A (PKA) is a biologically important enzyme for cell regulation, often referred to as the "central kinase". An immobilized PKA that retains substrate...
Protein kinase A (PKA) is a biologically important enzyme for cell regulation, often referred to as the "central kinase". An immobilized PKA that retains substrate specificity and activity would be a useful tool for laboratory scientists, enabling targeted phosphorylation without interference from downstream kinase contamination or kinase autophosphorylation in sensitive assays. Moreover, it might also provide the benefits of robustness and reusability that are often associated with immobilized enzyme preparations. In this work, we describe the creation of a recombinant PKA fusion protein that incorporates the HaloTag covalent immobilization system. We demonstrate that protein fusion design, including affinity tag placement, is critical for optimal heterologous expression in . Furthermore, we demonstrate various applications of our immobilized PKA, including the phosphorylation of recombinant PKA substrates, such as vasodilator-stimulated phosphoprotein, and endogenous PKA substrates in a cell lysate. This immobilized PKA also possesses robust activity and reusability over multiple trials. This work holds promise as a generalizable strategy for the production and application of immobilized protein kinases.
Topics: Protein Kinases; Phosphorylation; Recombinant Fusion Proteins; Cyclic AMP-Dependent Protein Kinases; Escherichia coli
PubMed: 36379001
DOI: 10.1021/acs.bioconjchem.2c00485 -
Molecular Neurobiology Dec 2021Ischemic stroke is the third leading cause of mortality worldwide, but its medical management is still limited to the use of thrombolytics as a lifesaving option.... (Review)
Review
Ischemic stroke is the third leading cause of mortality worldwide, but its medical management is still limited to the use of thrombolytics as a lifesaving option. Multiple molecular deregulations of the protein kinase family occur during the period of ischemia/reperfusion. However, experimental studies have shown that alterations in the expression of essential protein kinases and their pharmacological modulation can modify the neuropathological milieu and hasten neurophysiological recovery. This review highlights the role of key protein kinase members and their implications in the evolution of stroke pathophysiology. Activation of ROCK-, MAPK-, and GSK-3β-mediated pathways following neuronal ischemia/reperfusion injury in experimental conditions aggravate the neuropathology and delays recovery. Targeting ROCK, MAPK, and GSK-3β will potentially enhance myelin regeneration, improve blood-brain barrier (BBB) function, and suppress inflammation, which ameliorates neuronal survival. Conversely, protein kinases such as PKA, Akt, PKCα, PKCε, Trk, and PERK salvage neurons post-ischemia by mechanisms including enhanced toxin metabolism, restoring BBB integrity, neurotrophic effects, and apoptosis suppression. Certain protein kinases such as ERK1/2, JNK, and AMPK have favourable and unfavourable effects in salvaging ischemia-injured neurons. Targeting multiple protein kinase-mediated pathways simultaneously may improve neuronal recovery post-ischemia.
Topics: Animals; Blood-Brain Barrier; Brain; Humans; Ischemic Stroke; Neurons; Protein Kinases
PubMed: 34549335
DOI: 10.1007/s12035-021-02563-y -
Annual Review of Genetics Nov 2021The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple...
The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.
Topics: Apoptosis; Humans; Necroptosis; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 34813352
DOI: 10.1146/annurev-genet-071719-022748