ArticleJournal of the American Chemical Society2017
Total Chemical Synthesis and Folding of All-l and All-d Variants of Oncogenic KRas(G12V).
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 55 citations in OpenAlex.
- Advances in the chemical synthesis of human proteoforms.Science China. Life sciences · 2025Review
- Backbone Protecting Groups for Enhanced Peptide and Protein Synthesis.Angewandte Chemie (International ed. in English) · 2025Review
- Selective Activation of Peptide-Thioester Precursors for Templated Native Chemical Ligations.Angewandte Chemie (International ed. in English) · 2025Article
- Polypeptide Preparation by β-Lactone-Mediated Chemical Ligation.Organic letters · 2024Article
- Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins.Nature communications · 2024Article
- Article
- Synthesis and applications of mirror-image proteins.Nature reviews. Chemistry · 2023Review
- Rational design of the genetic code expansion toolkit forFrontiers in genetics · 2023Article
- Article
- Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes.RSC advances · 2022Article
- Traceless Click-Assisted Native Chemical Ligation Enabled by Protecting Dibenzocyclooctyne from Acid-Mediated Rearrangement with Copper(I).Bioconjugate chemistry · 2021Article
- Article
- A straightforward methodology to overcome solubility challenges for N-terminal cysteinyl peptide segments used in native chemical ligation.Chemical science · 2021Article
- Novel protein science enabled by total chemical synthesis.Protein science : a publication of the Protein Society · 2019Review
- Xenoprotein engineering via synthetic libraries.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Exceptionally high-affinity Ras binders that remodel its effector domain.The Journal of biological chemistry · 2018Article
- Sortase-mediated chemical protein synthesis reveals the bidentate binding of bisphosphorylated p62 with K63 diubiquitin.Chemical science · 2017Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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