Investigating the Structure and Dynamics of the PIK3CA Wild-Type and H1047R Oncogenic Mutant. Gkeka, P., Evangelidis, T., Pavlaki, M., Lazani, V., Christoforidis, S., Agianian, B., & Cournia, Z. PLoS Comput Biol, 10(10):e1003895, October, 2014. ![Investigating the Structure and Dynamics of the PIK3CA Wild-Type and H1047R Oncogenic Mutant [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Author Summary The PI3Kα protein is involved in cellular processes such as cell growth, division, and formation of new blood vessels (angiogenesis) that aid cancer cell survival. In certain types of cancer cells, PI3Kα is found to be altered compared to healthy cells. These PI3Kα alterations, called mutations, are found in 27% of breast cancer patients, 24% of endometrial cancer patients, and 15% of colon cancer patients. PI3Kα mutations cause the protein to become overactivated and may contribute to tumor growth. The most common PI3Kα amino acid mutation is a histidine changed to an arginine: H1047R. Understanding how the H1047R mutation overactivates PI3Kα is central to developing therapeutics for cancer patients who bear PI3Kα mutations. To this end, we performed simulations and experiments of the mutated and physiological proteins to explain why the mutant protein becomes overactivated. Our results indicate structural and dynamical differences between the mutant and physiological proteins that may affect the PI3Kα function. Based on these differences, we propose a mechanism that highlights the series of events that lead to the mutant H1047R PI3Kα overactivation. This study provides insights into developing mutant-specific PI3Kα inhibitors that exploit the altered conformation of the mutant with respect to the physiological protein.
@article{gkeka_investigating_2014,
title = {Investigating the {Structure} and {Dynamics} of the {PIK}3CA {Wild}-{Type} and {H}1047R {Oncogenic} {Mutant}},
volume = {10},
url = {http://dx.doi.org/10.1371/journal.pcbi.1003895},
doi = {10.1371/journal.pcbi.1003895},
abstract = {Author Summary The PI3Kα protein is involved in cellular processes such as cell growth, division, and formation of new blood vessels (angiogenesis) that aid cancer cell survival. In certain types of cancer cells, PI3Kα is found to be altered compared to healthy cells. These PI3Kα alterations, called mutations, are found in 27\% of breast cancer patients, 24\% of endometrial cancer patients, and 15\% of colon cancer patients. PI3Kα mutations cause the protein to become overactivated and may contribute to tumor growth. The most common PI3Kα amino acid mutation is a histidine changed to an arginine: H1047R. Understanding how the H1047R mutation overactivates PI3Kα is central to developing therapeutics for cancer patients who bear PI3Kα mutations. To this end, we performed simulations and experiments of the mutated and physiological proteins to explain why the mutant protein becomes overactivated. Our results indicate structural and dynamical differences between the mutant and physiological proteins that may affect the PI3Kα function. Based on these differences, we propose a mechanism that highlights the series of events that lead to the mutant H1047R PI3Kα overactivation. This study provides insights into developing mutant-specific PI3Kα inhibitors that exploit the altered conformation of the mutant with respect to the physiological protein.},
number = {10},
urldate = {2016-01-13TZ},
journal = {PLoS Comput Biol},
author = {Gkeka, Paraskevi and Evangelidis, Thomas and Pavlaki, Maria and Lazani, Vasiliki and Christoforidis, Savvas and Agianian, Bogos and Cournia, Zoe},
month = oct,
year = {2014},
pages = {e1003895}
}
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