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相关概念视频

The Ras Gene02:38

The Ras Gene

6.2K
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...
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Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
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mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

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The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
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PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

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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...
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MAPK Signaling Cascades01:07

MAPK Signaling Cascades

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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...
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Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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相关实验视频

Updated: Jun 4, 2025

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

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解码KRAS动态:探索突变和抑制剂结合的影响.

Divya Pandey1, Kuldeep K Roy1

  • 1Department of Pharmaceutical Sciences, School of Health Sciences and Technology, UPES, Dehradun, 248007, Uttarakhand, India.

Archives of biochemistry and biophysics
|December 22, 2024
PubMed
概括

克拉斯G12C和G12D突变在不活跃状态下被AMG-510和MRTX1133.3等抑制剂稳定. 性AMG-510更有效地锁定了KRAS G12C,稳定了Switch-II口袋中的关键氨基酸.

科学领域:

  • 生物化学 生物化学
  • 分子生物学分子生物学
  • 药理学 药理学是指药理学的学科.

背景情况:

  • KRAS突变,特别是G12C和G12D,是人类癌症的普遍驱动因素.
  • 以前被认为是无法治疗的,KRAS突变现在被特定的抑制剂所准.
  • 了解KRAS的结构动态对于开发有效的癌症疗法至关重要.

研究的目的:

  • 研究KRAS G12C和G12D突变如何稳定活性状态.
  • 阐明KRAS抑制剂在非活性状态中锁定突变形状的机制.
  • 为了比较共价 (AMG-510) 和非共价 (MRTX1133) 抑制剂的稳定作用.

主要方法:

  • 野生类型和突变KRAS的多分子动力学 (MD) 模拟.
  • 分析蛋白质构造,结合点动态和Cα原子距离.
  • 每个残留物的能量分解以评估结合点的稳定性.

主要成果:

  • 与GDP相关的KRAS G12C和G12D突变在不活跃状态下分别被AMG-510和MRTX1133稳定.
  • 与非共价MRTX1133.3相比,共价AMG-510证明了KRAS G12C的优越稳定性,而非共价MRTX1133.
  • 抑制剂结合导致稳定的Cα原子距离,并减少了Switch-II口袋残留物中的能量变化.
关键词:
癌症 癌症 癌症 癌症克拉斯 (Kras) 是一个国家.克拉斯抑制剂是克拉斯抑制剂.分子动力学分子动力学突变突变是一种突变.这是一种RAS蛋白质.

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

  • 克拉斯抑制剂有效地将瘤突变锁定在不活跃的形状中.
  • AMG-510的共价结合为KRAS G12C突变提供了增强的稳定性.
  • 这些发现为设计针对KRAS的新型癌症药物提供了宝贵的见解.