GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf
| العنوان: | GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf |
|---|---|
| المؤلفون: | Shizhong Dai, Hiroaki Suga, D. Matthew Peacock, Kevan M. Shokat, Rong Gao, Ziyang Zhang, Qi Hu, Hayden Peacock |
| المصدر: | ACS central science, vol 6, iss 10 ACS Central Science ACS Central Science, Vol 6, Iss 10, Pp 1753-1761 (2020) |
| بيانات النشر: | eScholarship, University of California, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | chemistry.chemical_classification, GTP', Stereochemistry, General Chemical Engineering, Mutant, Wild type, Peptide, General Chemistry, Cyclic peptide, Amino acid, Residue (chemistry), Chemistry, chemistry, Chemical Sciences, Threonine, QD1-999, Research Article, Cancer |
| الوصف: | We report the identification of three cyclic peptide ligands of K-Ras(G12D) using an integrated in vitro translation–mRNA display selection platform. These cyclic peptides show preferential binding to the GTP-bound state of K-Ras(G12D) over the GDP-bound state and block Ras-Raf interaction. A co-crystal structure of peptide KD2 with K-Ras(G12D)·GppNHp reveals that this peptide binds in the Switch II groove region with concomitant opening of the Switch II loop and a 40° rotation of the α2 helix, and that a threonine residue (Thr10) on KD2 has direct access to the mutant aspartate (Asp12) on K-Ras. Replacing this threonine with non-natural amino acids afforded peptides with improved potency at inhibiting the interaction between Raf1-RBD and K-Ras(G12D) but not wildtype K-Ras. The union of G12D over wildtype selectivity and GTP state/GDP state selectivity is particularly desirable, considering that oncogenic K-Ras(G12D) exists predominantly in the GTP state in cancer cells, and wildtype K-Ras signaling is important for the maintenance of healthy cells. We report the discovery of GTP-state-selective cyclic peptide ligands of K-Ras(G12D), a prevalent oncogenic driver, using an integrated in vitro translation−mRNA display selection platform. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b842b4def3cc7ec49dc227c4ced26c29 https://escholarship.org/uc/item/1px9b79x |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b842b4def3cc7ec49dc227c4ced26c29 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |