The organisational structure of class A GPCRs: Implications for function and drug design

用于治疗心力衰竭、血压升高、哮喘和精神分裂症等广泛疾病的相当一部分治疗药物通过激活或抑制称为G蛋白偶联受体的蛋白质家族成员发挥作用。这些细胞识别细胞外激素和神经递质的存在，并将这些信息转化为允许细胞做出反应的信号。除了G蛋白偶联受体家族的成员是目前药物的分子靶点之外，还有更多的成员正在积极探索，以了解其功能的细节及其在疾病发展或调节中的潜在作用。多年来，人们一直认为G蛋白偶联受体作为单体存在并发挥作用。然而，最近的一系列研究表明，这可能是不正确的，除了与自身相互作用形成同源二聚体外，存在于同一细胞中的G蛋白偶联受体家族的不同成员也可能相互作用形成异源二聚体。这可能对理解目前使用的药物的作用，更重要的是，对识别和开发新型治疗药物的方式产生重要影响。该提案计划建立在我和我的团队在过去5年中在这一领域开发的见解的基础上，以了解G蛋白偶联受体同源和异源二聚体形成的方式和位置的分子基础，并可能受到调节，并利用许多异源二聚体选择性配体的鉴定来了解这种选择性的基础。这可能有助于开发具有更大选择性和更有限副作用的新药。

A substantial fraction of therapeutic medicines that are used to treat conditions as wide ranging as heart failure, elevated blood pressure, asthma, and schizophrenia act by either activating or inhibiting members of a family of proteins known as G protein-coupled receptors. These recognise the presence of extracellular hormones and neuro-transmitters and convert this information into signals that allow cells to respond. As well as the members of the G protein-coupled receptor family that are the molecular targets of current medicines, there are many more that are being actively explored to understand the details of their function and their potential roles in the development or modulation of disease. For many years it was considered that G protein-coupled receptors existed and functioned as monomers. However, a wide range of recent studies have indicated that this is probably incorrect and that as well as interacting with themselves to form homo-dimers, different members of the G protein-coupled receptor family that are present in the same cell may interact to form hetero-dimers. This may have important consequences both for understanding the action of currently used drugs and, more importantly, in the manner in which novel therapeutic medicines are identified and developed. The proposal plans to build on the insights my team and I have developed in this area over the past 5 years to understand the molecular basis of how and where G protein-coupled receptor homo-and hetero-dimers form and may be regulated and to take advantage of the identification of a number of hetero-dimer-selective ligands to understand the basis of this selectivity. This is likely to contribute to the development of novel medicines with greater selectivity and more limited side effects.