6WGN

Crystal structure of K-Ras(G12D) GppNHp bound to cyclic peptide ligand KD2

Summary for 6WGN

• Entry DOI: 10.2210/pdb6wgn/pdb
• Descriptor: GTPase KRas, Cyclic Peptide KD2, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (5 entities in total)
• Functional Keywords: inhibitor, k-ras, selective, cyclic peptide, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 65224.00

Authors

Zhang, Z.,Gao, R.,Hu, Q.,Peacock, H.,Peacock, D.M.,Shokat, K.M.,Suga, H. (deposition date: 2020-04-06, release date: 2020-10-14, Last modification date: 2024-11-06)

Primary citation

Zhang, Z.,Gao, R.,Hu, Q.,Peacock, H.,Peacock, D.M.,Dai, S.,Shokat, K.M.,Suga, H.
GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf.
Acs Cent.Sci., 6:1753-1761, 2020

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

PubMed: 33145412
DOI: 10.1021/acscentsci.0c00514

Experimental method

X-RAY DIFFRACTION (1.601 Å)