Allosteric regulation of kinase activity in living cells
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 di...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-11-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/90574 |
| _version_ | 1797633095362412544 |
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| author | Shivani Sujay Godbole Nikolay V Dokholyan |
| author_facet | Shivani Sujay Godbole Nikolay V Dokholyan |
| author_sort | Shivani Sujay Godbole |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T11:45:56Z |
| format | Article |
| id | doaj.art-bfad949894844eb68f9ea58fc6aa2484 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T11:45:56Z |
| publishDate | 2023-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-bfad949894844eb68f9ea58fc6aa24842023-11-09T13:27:57ZengeLife Sciences Publications LtdeLife2050-084X2023-11-011210.7554/eLife.90574Allosteric regulation of kinase activity in living cellsShivani Sujay Godbole0https://orcid.org/0000-0002-0177-2286Nikolay V Dokholyan1https://orcid.org/0000-0002-8225-4025Department of Pharmacology, Penn State College of Medicine, Hershey, United StatesDepartment of Pharmacology, Penn State College of Medicine, Hershey, United States; Department of Biomedical Engineering, Penn State University, University Park, Hershey, United States; Department of Engineering Science and Mechanics, Penn State University, University Park, Hershey, United States; Department of Biochemistry & Molecular Biology, Penn State College of Medicine, Hershey, United States; Department of Chemistry, Penn State University, University Park, Hershey, United StatesThe 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.https://elifesciences.org/articles/90574protein kinaseallosterymolecular dynamics simulationsprotein engineering |
| spellingShingle | Shivani Sujay Godbole Nikolay V Dokholyan Allosteric regulation of kinase activity in living cells eLife protein kinase allostery molecular dynamics simulations protein engineering |
| title | Allosteric regulation of kinase activity in living cells |
| title_full | Allosteric regulation of kinase activity in living cells |
| title_fullStr | Allosteric regulation of kinase activity in living cells |
| title_full_unstemmed | Allosteric regulation of kinase activity in living cells |
| title_short | Allosteric regulation of kinase activity in living cells |
| title_sort | allosteric regulation of kinase activity in living cells |
| topic | protein kinase allostery molecular dynamics simulations protein engineering |
| url | https://elifesciences.org/articles/90574 |
| work_keys_str_mv | AT shivanisujaygodbole allostericregulationofkinaseactivityinlivingcells AT nikolayvdokholyan allostericregulationofkinaseactivityinlivingcells |