Allosteric regulation of kinase activity in living cells
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Curated by eLife
eLife assessment
One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important paper reviews convincingly the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.
This article has been Reviewed by the following groups
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- Evaluated articles (eLife)
- Structural Biology and Molecular Biophysics (eLife)
Abstract
The dysregulation of protein kinases is associated with multiple diseases due to the kinases' involvement in a variety of cell signaling pathways. Manipulating protein kinase function, by controlling the active site, is a promising therapeutic and investigative strategy to mitigate and study diseases. Kinase active sites share structural similarities, making it difficult to specifically target one kinase, and allosteric control allows specific regulation and study of kinase function without directly targeting the active site. Allosteric sites are distal to the active site but coupled via a dynamic network of inter-atomic interactions between residues in the protein. Establishing an allosteric control over a kinase requires understanding the allosteric wiring of the protein. Computational techniques offer effective and inexpensive mapping of the allosteric sites on a protein. Here, we discuss the methods to map and regulate allosteric communications in proteins, and strategies to establish control over kinase functions in live cells and organisms. Protein molecules, or ‘sensors,’ are engineered to function as tools to control allosteric activity of the protein as these sensors have high spatiotemporal resolution and help in understanding cell phenotypes after immediate activation or inactivation of a kinase. Traditional methods used to study protein functions, such as knockout, knockdown, or mutation, cannot offer a sufficiently high spatiotemporal resolution. We discuss the modern repertoire of tools to regulate protein kinases as we enter a new era in deciphering cellular signaling and developing novel approaches to treat diseases associated with signal dysregulation.
Article activity feed
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Author Response
The following is the authors’ response to the previous reviews
Comments from reviewer 1:
Comment 1. Regarding SBSMMA, the authors may complement their discussion by mentioning recent work (PMID: 35738428) where SBSMMA was used to exemplify a potential fragment-based design approach for developing allosteric effectors for kinases.
Thank you for the suggestion, we have added a short summary of the work where SBSMMA is used as a basis for developing small molecules to target kinases using fragment-based design approach
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eLife assessment
One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important paper reviews convincingly the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.
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Joint Public Review:
This concise review provides a clear and instructive picture of the state-of-the-art understanding of protein kinases' activity and sets of approaches and tools to analyse and regulate it.
Three major parts of the work include: methods to map allosteric communications, tools to control allostery, and allosteric regulation of protein kinases. The work provides an important and timely view of the current status of our understanding of the function of protein kinases and state-of-the-art methods to study its allosteric regulation and to develop allosteric approaches to control it.
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Author Response
The following is the authors’ response to the original reviews.
We thank the reviewers for their generous comments on the manuscript and have made edits to address their concerns. The manuscript has been restructured and the reference (PMID: 35738428) has been added to the review. We addressed the reviewer's comment below.
Reviewer #1 (Recommendations For The Authors):
Regarding SBSMMA, the authors may complement their discussion by mentioning recent work (PMID: 35738428) where SBSMMA was used to exemplify a potential fragment-based design approach for developing allosteric effectors for kinases.
Thank you for the suggestion, we have added a short summary of the work where SBSMMA is used as a basis for developing small molecules to target kinases using fragment-based design approach.
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eLife assessment
One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important manuscript provides a convincing review of the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.
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Joint Public Review:
This concise review provides a clear and instructive picture of the state-of-the-art understanding of protein kinases' activity and sets of approaches and tools to analyse and regulate it.
Three major parts of the work include: methods to map allosteric communications, tools to control allostery, and allosteric regulation of protein kinases. The work provides an important and timely view of the current status of our understanding of the function of protein kinases and state-of-the-art methods to study its allosteric regulation and to develop allosteric approaches to control it.
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eLife assessment
One of the most promising strategies in development of drugs targeting kinases is provided by using allosteric control that allows specific regulation and study of kinase function without directly targeting the active site. This important work reviews convincingly the current repertoire of tools for regulating the activity of protein kinases with the ultimate goal of developing novel approaches in treating diseases associated with signal dysregulation.
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Joint Public Review:
Summary:
This concise review provides a clear and instructive picture of the state-of-the-art understanding of protein kinases' activity and sets of approaches and tools to analyse and regulate it.
Strengths:
Three major parts of the work include: methods to map allosteric communications, tools to control allostery, and allosteric regulation of protein kinases. The work provides an important and timely view of the current status of our understanding of the function of protein kinases and state-of-the-art methods to study its allosteric regulation and to develop allosteric approaches to control it.
Weaknesses:
The authors may wish to consider first discussing the allosteric regulation of kinases, which can be further considered from the perspective of computational approaches to map and experimental methods to …
Joint Public Review:
Summary:
This concise review provides a clear and instructive picture of the state-of-the-art understanding of protein kinases' activity and sets of approaches and tools to analyse and regulate it.
Strengths:
Three major parts of the work include: methods to map allosteric communications, tools to control allostery, and allosteric regulation of protein kinases. The work provides an important and timely view of the current status of our understanding of the function of protein kinases and state-of-the-art methods to study its allosteric regulation and to develop allosteric approaches to control it.
Weaknesses:
The authors may wish to consider first discussing the allosteric regulation of kinases, which can be further considered from the perspective of computational approaches to map and experimental methods to control it.
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