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

当前位置： X-MOL 学术 › ACS Cent. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf
ACS Central Science ( IF 12.7 ) Pub Date : 2020-09-23 , DOI: 10.1021/acscentsci.0c00514
Ziyang Zhang ₁ , Rong Gao ₂ , Qi Hu ₁ , Hayden Peacock ₂ , D. Matthew Peacock ₁ , Shizhong Dai ₁ , Kevan M. Shokat ₁ , Hiroaki Suga ₂

Affiliation

We report the identification of three cyclic peptide ligands of K-Ras(G12D) using an integrated in vitro 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.

中文翻译：

GTP状态的K-Ras（G12D）的选择性环肽配体阻止其与Raf的相互作用。

我们报告使用集成的体外K-Ras（G12D）的三个环肽配体的鉴定翻译-mRNA展示选择平台。这些环状肽与K-Ras（G12D）的GTP结合状态相比，与GDP结合状态优先结合，并阻止Ras-Raf相互作用。肽KD2与K-Ras（G12D）·GppNHp的共晶体结构表明，该肽在Switch II凹槽区域结合，同时伴随着Switch II环的打开和α2螺旋的40°旋转，苏氨酸KD2上的残基（Thr10）可直接进入K-Ras上的突变型天冬氨酸（Asp12）。用非天然氨基酸代替该苏氨酸可提供具有提高的抑制Raf1-RBD与K-Ras（G12D）之间相互作用的能力的肽，但不能抑制野生型K-Ras。特别需要将G12D与野生型选择性和GTP状态/ GDP状态选择性结合起来，

更新日期：2020-10-29

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11