GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf

• DOI: 10.1021/acscentsci.0c00514
• Publication Date: 2020-09-23T18:59:48Z
• Authors: Ziyang Zhang; Rong Gao; Qi Hu; Hayden Peacock; D. Matthew Peacock; Shizhong Dai; Kevan M. Shokat; Hiroaki Suga
• Keywords: Tripeptide; Wild type

We report the identification of three cyclic peptide ligands K-Ras(G12D) using an integrated in vitro translation–mRNA display selection platform. These peptides show preferential binding to GTP-bound state over GDP-bound and block Ras-Raf interaction. A co-crystal structure KD2 with K-Ras(G12D)·GppNHp reveals that this binds Switch II groove region concomitant opening loop a 40° rotation α2 helix, threonine residue (Thr10) on has direct access mutant aspartate (Asp12) K-Ras. Replacing non-natural amino acids afforded improved potency at inhibiting interaction between Raf1-RBD but not wildtype The union G12D selectivity GTP state/GDP is particularly desirable, considering oncogenic exists predominantly cancer cells, K-Ras signaling important for maintenance healthy cells.