Sogabe Satoshi, Kamada Yusuke, Miwa Masanori, Niida Ayumu, Sameshima Tomoya, Kamaura Masahiro, Yonemori Kazuko, Sasaki Shigekazu, Sakamoto Jun-Ichi, Sakamoto Kotaro
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
ACS Med Chem Lett. 2017 May 10;8(7):732-736. doi: 10.1021/acsmedchemlett.7b00128. eCollection 2017 Jul 13.
The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein-protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors.
Ras蛋白在细胞分化、增殖和存活中发挥作用。肿瘤细胞中通过Ras介导的信号通路发生异常信号传导是几种类型的突变损伤的结果，其中最常见的是影响氨基酸G12、G13和Q61。最近，KRpep-2d被鉴定为针对K-Ras的G12D突变体的K-Ras(G12D)选择性抑制肽，K-Ras是Ras蛋白家族的关键成员，也是一个有吸引力的癌症治疗靶点。在本研究中，以1.25 Å的分辨率测定了人K-Ras(G12D)突变体与GDP和KRpep-2d复合物的晶体结构。该结构表明，该肽在Switch II附近结合，并通过变构作用阻断与鸟嘌呤核苷酸交换因子的蛋白质-蛋白质相互作用。这一独特结合口袋的发现提供了有价值的信息，将有助于设计直接的Ras抑制剂。
