دورية أكاديمية
α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death
| العنوان: | α4-α5 Helices on Surface of KRAS Can Accommodate Small Compounds That Increase KRAS Signaling While Inducing CRC Cell Death |
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| المؤلفون: | Baraa Abuasaker, Eduardo Garrido, Marta Vilaplana, Jesús Daniel Gómez-Zepeda, Sonia Brun, Marta Garcia-Cajide, Caroline Mauvezin, Montserrat Jaumot, Maria Dolors Pujol, Jaime Rubio-Martínez, Neus Agell |
| المصدر: | International Journal of Molecular Sciences, Vol 24, Iss 1, p 748 (2023) |
| بيانات النشر: | MDPI AG, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Biology (General) LCC:Chemistry |
| مصطلحات موضوعية: | colorectal cancer, KRAS, molecular dynamics, docking, allosteric pocket, calmodulin, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the α4-α5 helices of the allosteric domain of KRAS. This region had previously been identified as the binding site for calmodulin (CaM). Using surface plasmon resonance and pulldown analyses, we prove that P14B binds directly to oncogenic KRAS thus competing with CaM. Interestingly, P14B favors oncogenic KRAS interaction with BRAF and phosphorylated C-RAF, and increases downstream Ras signaling in CRC cells expressing oncogenic KRAS. The viability of these cells, but not that of the normal cells, is impaired by P14B treatment. These data support the significance of the α4-α5 helices region of KRAS in the regulation of oncogenic KRAS signaling, and demonstrate that drugs interacting with this site may destine CRC cells to death by increasing oncogenic KRAS downstream signaling. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1422-0067 1661-6596 |
| Relation: | https://www.mdpi.com/1422-0067/24/1/748; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067 |
| DOI: | 10.3390/ijms24010748 |
| URL الوصول: | https://doaj.org/article/b37dca4cc01e466184cf97793aaabb57 |
| رقم الأكسشن: | edsdoj.b37dca4cc01e466184cf97793aaabb57 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14220067 16616596 |
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| DOI: | 10.3390/ijms24010748 |