Tena-Campos Merce, Ramon Eva, Rivera Diana, Borroto-Escuela Dasiel O, Romero-Fernandez Wilber, Fuxe Kjell, Garriga Pere
Centre de Biotecnologia Molecular, Departament d'Enginyeria Química, Universitat Politecnica de Catalunya, Rambla St. Nebridi Nº22, 08222, Terrassa, Catalonia, Spain.
Curr Protein Pept Sci. 2014;15(7):648-58. doi: 10.2174/1389203715666140901094248.
G-protein-coupled receptors (GPCRs) are a widespread family of transmembrane receptors with different physiologically relevant functions. Alterations in the structure and function of these receptors at different levels (ligand binding, signaling and trafficking) may result in a number of pathological conditions which represent a major health problem. Mutations in these receptors are also linked to different inherited diseases for which there is no cure to date. Rationale design, based on receptor structural knowledge, is needed for the discovery of novel drugs with higher selectivity and less side effects. In fact, about 50% of the drugs currently under development target this kind of receptors. Oligomerization among GPCRs has been clearly established from experimental, particularly in vitro, studies. Moreover, homo and heterodimerization provide new unexpected clues for explaining the molecular mechanisms underlying some diseases in which GPCRs signaling might be affected. In this review we will analyze GPCRs structure and function for a better understanding of the dimerization process and the experimental approaches currently used to detect such interactions. Furthermore, how drugs targeting heteromers can represent new opportunities to tackle novel and safer treatments of some pathologies will be described. Recent results, in this regard, will be reported as encouraging examples in the field. Finally, the newest technologies available for developing drugs targeting heteromers will also be reviewed highlighting the importance of bivalent ligands that emerge as very powerful molecules interacting with heteromers.
G蛋白偶联受体（GPCRs）是一类广泛存在的跨膜受体家族，具有不同的生理相关功能。这些受体在不同水平（配体结合、信号传导和转运）的结构和功能改变可能导致许多病理状况，这是一个重大的健康问题。这些受体的突变还与目前尚无治愈方法的不同遗传性疾病有关。基于受体结构知识的合理设计对于发现具有更高选择性和更少副作用的新型药物是必要的。事实上，目前正在研发的药物中约有50%靶向这类受体。GPCRs之间的寡聚化已通过实验，特别是体外研究明确证实。此外，同源和异源二聚化提供了新的意外线索，用于解释一些可能影响GPCRs信号传导的疾病的分子机制。在这篇综述中，我们将分析GPCRs的结构和功能，以便更好地理解二聚化过程以及目前用于检测此类相互作用的实验方法。此外，还将描述靶向异聚体的药物如何为解决某些疾病的新型和更安全治疗提供新机会。在这方面，最新结果将作为该领域令人鼓舞的例子进行报道。最后，还将综述用于开发靶向异聚体药物的最新技术，强调作为与异聚体相互作用的非常强大分子出现的二价配体的重要性。
