RUI: Allosteric Activators of the Sarco/Endoplasmic Reticulum Calcium ATPase

在化学系生命过程化学项目的支持下，萨克拉门托州立大学的Stefan Paula正在研究能够刺激一种酶的活性的小分子的开发，这种酶的自然功能是跨细胞膜运输钙离子，即肌浆/内质网钙ATPase(SERCA)。使用这种新的小分子来调节SERCA酶的活性，将使研究人员能够观察细胞内钙浓度变化的影响。这些新分子旨在增强酶的活性，因此将补充一类已知的降低SERCA活性的分子。这项研究将涉及对学生进行生物分子化学研究中经常使用的各种技术的培训。作为该项目的一部分，分子建模技术和特定化合物的合成将被纳入萨克拉门托州立大学的三门高级课程。细胞内钙水平受到SERCA等钙转运体的严格控制，因为它们是许多细胞过程的关键调节因子。这个项目的主要目标是开发调节肌浆网/内质网钙ATPase(SERCA)活性的小分子。具体地说，Paula研究小组的目标是建立第一个不调节SERCA活性的化学生物学工具，以研究生物体内细胞内钙水平增加或减少的影响。虽然使用SERCA抑制剂作为研究工具已经很久了，但激活剂到目前为止还很少受到关注。利用计算和实验方法的协同结合，该项目试图通过产生新的SERCA激活剂，在分子水平上建立SERCA激活的分子决定因素，并在体内评估新化合物来缩小这一差距。潜在的SERCA激活剂的有机合成、纯化的SERCA的活性分析、分子模拟和基于细胞的分析将被用于实现这些研究目标。这项计划中的研究似乎是对SERCA激活剂的第一次系统探索，预计将提供SERCA-配体结构-活性关系空间的有价值的知识和潜在的非常有价值的化学生物学工具。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes Program in the Division of Chemistry, Stefan Paula of Sacramento State University is studying the development of small molecules capable of stimulating the activity of an enzyme whose natural function is the transport of calcium ions across cell membranes; namely the sarco/endoplasmic reticulum calcium ATPase (SERCA). Use of the novel small molecules to modulate the activity of the SERCA enzyme would allow the investigator to observe the effects of altered calcium concentrations inside the cell. The new molecules are designed to enhance enzyme activity and as such would complement a class of molecules known to reduce SERCA activity. The research will involve the training of students in a variety of techniques frequently employed in biomolecular chemistry research. As part of the project, molecular modeling techniques and the synthesis of specific compounds will be incorporated in three upper division courses at Sacramento State University.Intracellular calcium levels are tightly controlled by the action of calcium transporters such as SERCA because they are critical regulators of many cellular processes. The major goal of this project is the development of small molecules that modulate the activity of sarco/endoplasmic reticulum calcium ATPase (SERCA). Specifically, the Paula research group is aiming to establish the first tools for chemical biology that unregulate the activity of SERCA to study of the effects of increased or decreased intracellular calcium levels in living organisms. Whereas the use of SERCA inhibitors as research tools is well-established, activators have thus far received very little attention. Using a synergistic combination of computational and experimental approaches, the project seeks to close this gap by generating novel SERCA activators, establishing the molecular determinants for SERCA activation at the molecular level, and evaluating the new compounds in vivo. Organic synthesis of potential SERCA activators, activity assays with purified SERCA, molecular modeling, and cell-based assays are to be used to accomplish these research goals. The planned study appears to be the first systematic exploration of SERCA activators and is expected to provide valuable knowledge in SERCA-ligand structure-activity relationship space and potentially very valuable tools for chemical biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.