Allosteric Modulation of G Protein-Coupled Receptors

所有活细胞的正常功能取决于它们如何对不断暴露的大量物理和化学刺激作出反应。大多数作用于细胞的化学刺激不是通过直接进入细胞，而是通过作用于细胞表面被称为受体的特定类型的受体蛋白。一个重要的受体家族通过与另一种称为G蛋白的蛋白质偶联将信息传递到细胞内部。这些G蛋白偶联受体正常功能的异常与多种疾病有关，包括神经精神疾病、内分泌疾病、心血管疾病和许多癌症。迄今为止，大多数药物作用于G蛋白偶联受体是通过结合这些受体上的特定区域来实现的。尽管使用这种方法在疾病治疗方面取得了许多突破，但仍存在许多公认的局限性，包括缺乏药物选择性、毒性和长期治疗的反应性降低。我们目前的建议侧重于将药物靶向到G蛋白偶联受体的替代区域，这可能克服许多与当前药物治疗相关的局限性。了解这些替代药物结合位点的特性，将在我们目前的资助中进行研究，可以为各种疾病提供更有效的治疗方法。

The normal function of all living cells depends on how they respond to the multitude of physical and chemical stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by directly entering the cell, but rather by acting on specific types of receiver proteins on the cell's surface called receptors. One important family of receptors transmit their message to the inside of the cell by coupling to yet another type of protein known as the G protein. Aberrations in the normal function of these G protein-coupled receptors have been implicated in a wide variety of disorders, including neuropsychiatric conditions, endocrine disorders, cardiovascular disease and many cancers. To date, the majority of drugs acting at G protein-coupled receptors do so by binding to specific regions on these receptors. Although many breakthroughs in disease treatment have been achieved using this approach, there remain a number of acknowledged limitations, including lack of drug selectivity, toxicity and reduced responsiveness with prolonged therapy. Our current proposal focuses on targeting drugs to alternative regions of G protein-coupled receptors that may overcome many of the limitations associated with current drug therapies. An understanding of the properties of these alternative drug binding sites, which will be investigated in our current grant, can lead to more effective treatments for a variety of diseases.