Learte Aymamí, SorayaMartin-Malpartida, PauRoldán-Martín, LorenaSciortino, GiuseppeCouceiro, José R.Maréchal, Jean-DidierMacias, Maria JMascareñas Cid, José LuisVázquez Sentís, Marco Eugenio2022-06-302022-06-302022Learte-Aymamí, S.; Martin-Malpartida, P.; Roldán-Martín, L.; Sciortino, G. ; Couceiro, J. R. ; Maréchal, J.-D.; Macias, M. J.; Mascareñas, J. L.; Vázquez, M. E. (2022), Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide. Commun. Chem., 5: 75. doi: 10.1038/s42004-022-00691-72399-3669http://hdl.handle.net/10347/28863RAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the αH helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II). NMR spectroscopy and MD studies demonstrate that Pd(II) has a nucleating effect that facilitates the access to the bioactive α-helical conformation. The binding can be suppressed by an external metal chelator and recovered again by the addition of more Pd(II), making this system the first switchable KRAS binder, and demonstrates that folding-upon-binding mechanisms can operate in metal-nucleated peptides. In vitro experiments show that the metallopeptide can efficiently internalize into living cells and inhibit the MAPK kinase cascadeeng© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/journal article10.1038/s42004-022-00691-7open access