相关实验视频

Updated: May 22, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein

Published on: January 16, 2020

通过直接对 CaaX-box 半氨酸的共价攻击,阻止 KRAS4b 的 C-终端处理

Anna E Maciag¹, Yue Yang², Alok K Sharma¹

¹National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701.

Proceedings of the National Academy of Sciences of the United States of America

|May 9, 2025

概括

研究人员开发了针对KRAS4bb的新的共价修饰剂.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

在癌症中,RAS是一种经常发生突变的癌基因.
克拉斯4b蛋白与细胞膜通过由囊类残留物转化后修饰 (PTM) 形成的脂质相互作用.
克拉斯4b在位置185 (C185) 具有独特的氨酸,对于前化和膜附着至关重要.

研究的目的:

发现和开发针对KRAS4b.的C185的小分子共价修饰剂.
抑制KRAS4b前和随后的细胞膜附着,从而阻止其生物活性.
探索一种针对KRAS驱动的癌症的新治疗策略.

主要方法:

二硫化物联结屏幕的开发,进入不可逆转的共价变异剂中.
用于评估癌细胞增殖抑制的测试.
顶向下的蛋白质组学用于目标接触确认.
分子动力学模拟,小角度X射线散射和溶液NMR用于结构分析.
NOESY-HSQC的NMR实验以确定关键的残留物和相互作用.

主要成果:

开发的化合物抑制了KRAS4b驱动细胞的增殖,但不是C185S突变的细胞.
通过蛋白质组学在细胞中确认了向参与.
确定了一个结合口袋 (HVR-α3-α4),其中化合物与KRAS4b相互作用.
结构分析显示,在C185结合剂的存在下,口袋的稳定.

结论:

对C185的不可逆转的共价修饰是抑制KRAS4b的一种可行的策略.
HVR-α3-α4口袋是KRAS4b的一个可用药物的目标.
针对这个口袋的化合物的进一步开发可能会导致针对KRAS驱动的癌症的新疗法.

关键词:

在C185中,它是C185.高频视频录像机 (HVR) 是一个高频视频录像机.克拉斯 (Kras) 是一个国家.这就是KRAS4bb.作为一种共价抑制剂.

更多相关视频

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

相关概念视频

Caspases

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside...

Allosteric Proteins-ATCase

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...

The Ras Gene

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...

Anaphase Promoting Complex

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...

MAPK Signaling Cascades

MAPK Signaling Cascades

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...

PI3K/mTOR/AKT Signaling Pathway

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...