Filizola Marta, Weinstein Harel
Weill Medical College of Cornell University, Department of Physiology and Biophysics, New York, NY 10021, USA.
Curr Opin Drug Discov Devel. 2005 Sep;8(5):577-84.
G protein-coupled receptors (GPCRs) represent approximately half of the potential pharmaceutical targets for current drugs, and thus the way in which these receptors assemble into dimeric/oligomeric structures is of vital interest in practical as well as conceptual aspects of current drug discovery efforts. The significance of such structures is based on the recent realization that ligand-dependent signaling by GPCRs is not necessarily transduced to the G protein by receptor monomers, but possibly by GPCR dimers or even oligomers that function as dynamic macromolecular assemblies. In addition, recent evidence that GPCR hetero-oligomerization can produce signaling units with unexpected combinations of pharmacological properties suggests entirely new methods for developing successful drugs. The dynamic mechanisms of these signaling assemblies remain to be elucidated. The development of increasingly accurate dynamic molecular models of GPCR dimers is expected to produce a more complete structural context for understanding the molecular mechanisms of GPCR function, and to aid in drug discovery.
G蛋白偶联受体（GPCRs）约占当前药物潜在靶点的一半，因此这些受体组装成二聚体/寡聚体结构的方式在当前药物研发工作的实际和概念层面都至关重要。此类结构的重要性基于最近的认识，即GPCRs的配体依赖性信号传导不一定由受体单体传递给G蛋白，而是可能由作为动态大分子组装体的GPCR二聚体甚至寡聚体传递。此外，最近有证据表明GPCR异源寡聚化可产生具有意外药理学特性组合的信号传导单元，这为开发成功药物提供了全新方法。这些信号组装体的动态机制仍有待阐明。预计GPCR二聚体越来越精确的动态分子模型的发展将为理解GPCR功能的分子机制提供更完整的结构背景，并有助于药物研发。
