Unravelling the effect of the E545K mutation on PI3Kα kinase
| Autor: | Ioannis Galdadas, Zoe Cournia, Francesco Luigi Gervasio |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
ddc:615 Chemistry Kinase Mutant Lipid kinase activity Energy landscape Hotspot mutation General Chemistry E545K mutation medicine.disease_cause 3. Good health Cell biology 03 medical and health sciences Cancer development 0302 clinical medicine Signalling 030220 oncology & carcinogenesis medicine Carcinogenesis Mode of action 030304 developmental biology |
| Zdroj: | Chemical Science, Vol. 11, No 13 (2020) pp. 3511-3515 Chemical Science |
| ISSN: | 2041-6520 |
| Popis: | PI3Kα controls several cellular processes and its aberrant signalling is implicated in tumorigenesis. One of its hotspot mutations, E545K, increases PI3Kα lipid kinase activity, but its mode of action is only partially understood. Here, we perform biased and unbiased molecular dynamics simulations of PI3Kα and uncover, for the first time, the free energy landscape of the E545K PI3Kα mutant. We reveal the mechanism by which E545K leads to PI3Kα activation in atomic-level detail, which is considerably more complex than previously thought. The mechanism by which the cancer-causing E545K mutation may lead to PI3Kα activation is described in atomic-level detail. |
| Databáze: | OpenAIRE |
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