在非小细胞肺癌中对Apo和ATP-I1171N/S/T进行比较的原子化洞察
Ambritha Balasundaram1, George Priya C Doss1
1Laboratory of Integrative Genomics, Department of Integrative Biology, School of BioSciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India.
ACS omega
|November 29, 2023
概括
无细胞淋巴瘤激酶 (ALK) 突变I1171N/S/T促进一个独立于ATP结合的构成性活性激酶. 这种结构性洞察力有助于理解ALK的瘤性活性,并为非小细胞肺癌开发改进的ALK抑制剂.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 计算化学计算化学
背景情况:
- 在大约5%的非小细胞肺癌 (NSCLC) 患者中发现了无细胞淋巴瘤激酶 (ALK) 的重组,导致瘤的发展.
- 虽然像crizotinib这样的ALK抑制剂是有效的,但由于ALK激酶域的突变,耐药性往往会出现.
- 了解ALK激活和耐药性的结构机制对于开发下一代疗法至关重要.
研究的目的:
- 研究野生型 (WT) 形淋巴瘤激酶 (ALK) 和其I1171N/S/T突变变体的激活机制.
- 通过计算方法分析这些突变对腺三酸盐 (ATP) 结合和激酶构成的影响.
- 在药物耐药性背景下阐明构成性活性ALK激酶的结构基础.
主要方法:
- 采用分子对接和分子动力学模拟来分析ALK结构变化和ATP结合.
- 利用主要组件分析 (PCA) 和自由能源景观分析来评估结构稳定性和能源最小值.
- 执行了分子力学Poisson-Boltzmann表面积 (MM/PBSA) 计算,以确定结合能.
主要成果:
- 在ALK中的I1171N/S/T突变促进了向活性激酶构造转变,与非活性WT-Apo状态不同.
- 这些突变保持了活性激酶状态,独立于ATP结合,I1171S/T显示了与ATP增强的分子间键.
- MM/PBSA分析表明,突变ALK和WT-ALK与ATP之间的结合能是相似的,这表明了稳定的相互作用.
结论:
- I1171N/S/T突变赋予了一个构成性活跃的ALK激酶表型,可能有助于NSCLC的耐药性.
- 特定的相互作用,如I1171N突变中的Y1278-C1097H键和E1167-K1150盐桥,稳定了独立于ATP的活性状态.
- 这种结构性理解为设计更有效的ALK抑制剂以向耐药突变提供了基础.
更多相关视频
10:28A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors
Published on: August 17, 2019
9.6K
09:38Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
8.0K
相关概念视频
02:55The Nucleolus
8.9K
The nucleolus is the most prominent substructure of the nucleus. When it was first discovered, it was considered to be an isolated organelle that forms fibrils and granules. In 1931, the relationship between the nucleolus and chromosomes was first described by Heitz. He observed that the appearance and size of nucleolus varies depending on the stage of the cell cycle. He also noticed constricted regions on different chromosomes clustered together at definite cell cycle stages. These regions,...
8.9K
01:48ATP Synthase: Mechanism
14.7K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
14.7K
02:57Targeted Cancer Therapies
7.6K
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...
7.6K
01:18ATP Synthase: Structure
12.5K
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
12.5K