通过精确引导的弹头脚手架,准一个关键的蛋白质-蛋白质相互作用表面,以对基因激活蛋白激酶进行向
Ádám Levente Póti1,2, Dániel Bálint3,4, Anita Alexa1
1Biomolecular Interaction Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Budapest, Hungary.
Nature communications
|October 4, 2024
概括
研究人员开发了针对MAPK D-groove的新型合迈克尔受体. 这些化合物可逆地抑制蛋白质-蛋白质相互作用,为MAPK信号通路提供了一个新的治疗策略.
科学领域:
- 生物化学 生物化学
- 化学生物学 化学生物学
- 分子药理学分子药理学
背景情况:
- 线素激活蛋白激酶 (MAPKs) 使用D槽来结合蛋白质,与基质口袋不同.
- 准MAPK蛋白与蛋白相互作用对于调节信号通路至关重要.
研究的目的:
- 识别和描述可以抑制MAPK蛋白与蛋白相互作用的新型化合物.
- 探索奇拉迈克尔受容体作为向MAPK D-槽的共价抑制剂的潜力.
主要方法:
- 对迈克尔受体化合物的选,重点关注环色支架.
- 在体外结合亲和度测试以确定化合物的效力.
- 基于细胞的测试来评估MAPK信号网络的干扰.
主要成果:
- 一个固态拥挤的,性循环赫森分片被确定为一个有前途的支架.
- 化合物显示了保留的MAPK D-groove 半氨酸的可逆共价变异.
- 性中心的逆转改变了目标特异性,可能会与histidine接触.
- 在试验室中观察到低微分子结合亲和力,细胞通路扰乱.
结论:
- 带有增强的3D结构的状,循环的迈克尔接受器有效地准了MAPK D-groove.
- 这些化合物为调节MAPK信号提供了一种新的,非ATP竞争的方法.
- 这种支架为开发针对MAPK驱动疾病的治疗方法提供了一个有希望的替代方案.
相关概念视频
Assembly of Signaling Complexes
5.7K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
5.7K
MAPK Signaling Cascades
5.3K
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
5.3K
Targeted Cancer Therapies
7.5K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.5K
The JAK-STAT Signaling Pathway
8.7K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
8.7K


