6WGN

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

6WGN の概要

• エントリーDOI: 10.2210/pdb6wgn/pdb
• 分子名称: GTPase KRas, Cyclic Peptide KD2, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: inhibitor, k-ras, selective, cyclic peptide, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 65224.00

構造登録者

Zhang, Z.,Gao, R.,Hu, Q.,Peacock, H.,Peacock, D.M.,Shokat, K.M.,Suga, H. (登録日: 2020-04-06, 公開日: 2020-10-14, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.601 Å)