Editorial Board Member Professor Andy Wilson highlights Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide by Eugenio Vázquez, José Mascareñas and colleagues (https://doi.org/10.1038/s42004-022-00691-7). “This is a really nice interdisciplinary manuscript at the interface of chemical biology and supramolecular chemistry; it is beautifully presented and focuses as its centrepiece on the ability to reversibly nucleate an α-helix through coordination of histidine residues placed at the i and i + 4 positions in the peptide sequence with cis-protected palladium. The method is applied to target a key protein–protein interaction that activates the MAP kinase pathway—the interaction between RAS and its activator SOS1. RAS frequently misfunctions in human cancers and has become an important target for development of molecular therapeutics. What is particularly impressive about the paper is the broad range of experiments used; both circular dichroism and NMR are used for structure elucidation of the stimuli responsive peptide, then direct fluorescence anisotropy binding and nucleotide exchange assays used to characterize interaction with RAS and inhibition of the SOS1/RAS interaction, and then finally cell uptake is monitored alongside effects on the MAPK kinase cascade through inhibition of ERK phosphorylation. A further important concept is introduced, specifically that whilst the palladium clip induces some helicity in the peptide, this is only partial, but the effect is proposed to be sufficient to promote RAS binding (relative to the peptide in the absence of palladium) through a bind and fold mechanism similar to that through which many intrinsically disordered proteins operate. Overall, the paper comprises rigorous experimentation and introduces several new concepts. Given the widespread interest in the development of constrained peptides as protein–protein interaction inhibitors, this represents an important advance for the area of constrained peptides.”

Source: https://www.nature.com/articles/s42004-022-00795-0

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External link: https://www.nature.com/collections/efiidgdgfa