Allosteric inactivation of an engineered optogenetic GTPase

Jain, A. C.; Dokholyan, Nikolay V.; Lee, Andrew L.

doi:10.1073/pnas.2219254120

“…Lisi and Loria 51 described allostery using NMR studies paired with the computational predictions in enzyme catalysts; PTP1B (protein tyrosine phosphatase 1B) 52 , which is known to be associated with obesity and diabetes, and PKA-C (protein kinase C) 53 , which is responsible for cell signaling and proliferation. Jain et al 54 used NMR spectroscopy to configure the active and inactive structures of Cdc42-LOV2 construct. Light oxygen voltage (LOV2) protein is used as an optogenetic tool since it is active under blue light and is used to control protein function allosterically.…”

Section: Introductionmentioning

confidence: 99%

Allosteric regulation of kinase activity in living cells

Godbole

¹

,

Dokholyan

²

2023

Preprint

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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, 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 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.

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Allosteric regulation of kinase activity in living cells

Godbole,

Dokholyan

2023

eLife

0

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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, 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 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.

show abstract

Allosteric regulation of kinase activity in living cells

Godbole,

Dokholyan

2023

Preprint

0

View full text Add to dashboard Cite

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, 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 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.

show abstract

Allosteric inactivation of an engineered optogenetic GTPase

Cited by 6 publications

References 51 publications

Allosteric regulation of kinase activity in living cells

Allosteric regulation of kinase activity in living cells

Allosteric regulation of kinase activity in living cells

Allosteric regulation of kinase activity in living cells

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