在人类KRAS G13D中使用结构生物信息学和针对单克隆抗体的P循环发现了新的可药物化的空间
Oscar Jungholm1, Carolina Trkulja2,3, Martin Moche4
1Department of Physiology and Pharmacology, Karolinska Institutet, 171 77, Stockholm, Sweden.
Scientific reports
|August 23, 2024
概括
研究人员发现了KRAS G13D的新型,开放的构造,这是一个关键的癌症驱动突变. 一种已开发的抗体针对这种状态,证明了它的药用性和对新的结直肠癌疗法的潜力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- KRAS突变驱动各种癌症的瘤发生,包括结直肠癌 (CRC).
- 针对像G13D这样的KRAS突变是具有挑战性的,需要新的治疗策略.
- 了解难以捉摸的KRAS突变的结构格局对于药物开发至关重要.
研究的目的:
- 为了描述KRAS G13D的全新,完全开放的形状.
- 为了研究这个开放的KRAS G13D状态的可用性.
- 开发和验证一种针对KRAS G13D的治疗性抗体.
主要方法:
- 使用X射线晶体学,以1.42.4 Å分辨率确定KRAS G13D的结构.
- 开发了一种针对P循环的单克隆抗体 (mAb).
- 采用了高分辨率光显微镜,宏皮诺细胞检测,蛋白和基因组研究.
主要成果:
- 一个完全开放的,P-循环暴露的KRAS G13D的调节器被阐明.
- 克拉斯G13D开放式适配器显示了一个直立的开关I区域,暴露了催化芯.
- 开发的mAb显示了对KRAS G13D的高亲和度结合,并被G13D突变的CRC细胞内部化.
- 在细胞测试中,mAb有效抑制了KRAS信号传递.
结论:
- 这项研究提出了KRAS G13D.的新型,可药物开放的形状.
- 这种形状在细胞环境中是可访问的,提供了新的治疗机会.
- 这些发现支持开发基于抗体的或其他针对这种KRAS G13D状态的癌症治疗方法.
相关概念视频
01:15G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
01:26Drug Discovery: Overview
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...