PROTEIN CONFORMATION SAMPLING USING ENERGY LANDSCAPE APPROACH

使用能量景观方法进行蛋白质构象采样

• 批准号: 7358717
• 负责人: Peter Guy Wolynes
• 金额: $ 0.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358717
• 关键词: PROTEIN; CONFORMATION; SAMPLING; USING; ENERGY

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In mammalian cells, proteins are initially expressed as hetero-polymers with 20 types of different amino acids. Proteins, however, often need more varieties of subunits. This greater diversity is achieved by covalent post-translational modifications such as glycosylation, methylation, or nucleotidylation. These modifications can lead to conformational changes of the proteins by perturbing their energy landscape and thereby altering their functions. In this paper, we address the energetic and structural consequence of one of the most important forms of reversible modification: phosphorylation. In phosphopeptides, the side chain polar hydrogens of serine, threonine, tyrosine, and histidine can be replaced by phosphoryl groups. Phosphorylation occurs quite frequently in signal transduction regulation and is increasingly being noticed throughout the genome due to the advancements of mass spectrometry. Direct structural modifications not only may affect protein-protein interactions, but can allow conformational switches to be constructed using single domain proteins. Using the NFAT regulatory domain as an example, we show these changes can not only modify the secondary structure of the protein locally but also globally alter protein tertiary structure, thus allowing phosphorylation to reset the switch.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。在哺乳动物细胞中，蛋白质最初表达为具有 20 种不同氨基酸的杂聚物。然而，蛋白质通常需要更多种类的亚基。这种更大的多样性是通过共价翻译后修饰（例如糖基化、甲基化或核苷酸化）实现的。这些修饰可以扰乱蛋白质的能量格局，从而改变其功能，从而导致蛋白质的构象变化。 在本文中，我们讨论了可逆修饰最重要形式之一的能量和结构后果：磷酸化。在磷酸肽中，丝氨酸、苏氨酸、酪氨酸和组氨酸的侧链极性氢可以被磷酰基取代。磷酸化在信号转导调节中非常频繁地发生，并且由于质谱技术的进步，磷酸化在整个基因组中越来越受到关注。直接结构修饰不仅可能影响蛋白质-蛋白质相互作用，而且可以允许使用单结构域蛋白质构建构象转换。以 NFAT 调节域为例，我们证明这些变化不仅可以局部修改蛋白质的二级结构，还可以全局改变蛋白质的三级结构，从而允许磷酸化重置开关。