Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d

The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs because of several kinds of mutational damage, which most often affects the proteins G12, G13, and Q61. Lately, KRpep-2d was recognized as a K-Ras(G12D) selective inhibitory peptide from the G12D mutant of K-Ras, that is a key person in the Ras protein family as well as an attractive cancer therapeutic target. Within this study, the very structure from the human K-Ras(G12D) mutant was resolute in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure says the peptide binds near Switch II and allosterically blocks protein-protein interactions using the guanine nucleotide exchange factor. This KRpep-2d discovery of the unique binding pocket provides valuable information which will facilitate the style of direct Ras inhibitors.