Pfizer Boulder Research and Development, 3200 Walnut Street, Boulder, CO 80301, USA.
Acta Crystallogr F Struct Biol Commun. 2024 Sep 1;80(Pt 9):220-227. doi: 10.1107/S2053230X24007969. Epub 2024 Aug 28.
M-RAS plays a crucial role in the RAF-MEK signaling pathway. When activated by GTP, M-RAS forms a complex with SHOC2 and PP1C, initiating downstream RAF-MEK signal transduction. In this study, the crystal structure of the GDP-bound human M-RAS protein is presented with two forms of crystal packing. Both the full-length and truncated human M-RAS structures aligned well with the high-confidence section of the AlphaFold2-predicted structure with low r.m.s.d., except for the Switch regions. Despite high sequence similarity to the available mouse M-RAS structure, the full-length human M-RAS structure exhibits unique crystal packing. This inactive human M-RAS structure could offer novel insights for the design of selective compounds targeting M-RAS.
M-RAS 在 RAF-MEK 信号通路中起着至关重要的作用。当被 GTP 激活时，M-RAS 与 SHOC2 和 PP1C 形成复合物，启动下游 RAF-MEK 信号转导。在这项研究中，展示了 GDP 结合态的人源 M-RAS 蛋白的两种晶体包装形式。全长和截短的人源 M-RAS 结构与 AlphaFold2 预测结构的高置信度部分对齐良好，r.m.s.d. 较低，除了开关区域。尽管与现有的鼠源 M-RAS 结构具有高度的序列相似性，但全长人源 M-RAS 结构表现出独特的晶体包装。这种非活性的人源 M-RAS 结构为设计针对 M-RAS 的选择性化合物提供了新的见解。
