1. Главная
  2. Ресурсы
  3. Библиотечный поиск
Total ChemicalSynthesis and Foldingof All-l and All-dVariants of OncogenicKRas(G12V) Adam M. LevinsonJohn H. McGeeAndrew G. Roberts2017 год

Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V)
статья из журнала

Полный текстСтраница публикацииПубликация в OpenAlex
Аннотация: The Ras proteins are essential GTPases involved in the regulation of cell proliferation and survival. Mutated oncogenic forms of Ras alter effector binding and innate GTPase activity, leading to deregulation of downstream signal transduction. Mutated forms of Ras are involved in approximately 30% of human cancers. Despite decades of effort to develop direct Ras inhibitors, Ras has long been considered "undruggable" due to its high affinity for GTP and its lack of hydrophobic binding pockets. Herein, we report a total chemical synthesis of all-l- and all-d-amino acid biotinylated variants of oncogenic mutant KRas(G12V). The protein is synthesized using Fmoc-based solid-phase peptide synthesis and assembled using combined native chemical ligation and isonitrile-mediated activation strategies. We demonstrate that both KRas(G12V) enantiomers can successfully fold and bind nucleotide substrates and binding partners with observable enantiodiscrimination. By demonstrating the functional competency of a mirror-image form of KRas bound to its corresponding enantiomeric nucleotide triphosphate, this study sets the stage for further biochemical studies with this material. In particular, this protein will enable mirror-image yeast surface display experiments to identify all-d peptide ligands for oncogenic KRas, providing a useful tool in the search for new therapeutics against this challenging disease target.
Год издания: 2017
Авторы: Adam M. Levinson, John H. McGee, Andrew G. Roberts, Gardner S. Creech, Ting Wang, Michael Peterson, Ronald C. Hendrickson, Gregory L. Verdine, Samuel J. Danishefsky
Издательство: American Chemical Society
Источник: Journal of the American Chemical Society
Ключевые слова: Chemical Synthesis and Analysis, Protein Kinase Regulation and GTPase Signaling, Computational Drug Discovery Methods
Другие ссылки: Journal of the American Chemical Society (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)