School of Life Sciences, Jawaharlal Nehru University, New Delhi-110067.
Mini Rev Med Chem. 2013 Dec;13(14):2036-46. doi: 10.2174/13895575113139990079.
This Review deals essentially with the elucidation of structural features of Tachykinin family of neuropeptides, which are known to interact through three distinct GPCR subtypes, namely NK1 (Neurokinin 1), NK2 (Neurokinin 2) and NK3 (Neurokinin 3) receptors. In mammals, Tachykinins have been shown to elicit a wide array of activities such as powerful vasodilatation, hypertensive action and stimulation of extravascular smooth muscle and are known to be involved in a variety of clinical conditions including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma. This broad spectrum of action of Tachykinins is attributed to the lack of selectivity of tachykinins to their receptors. All tachykinins interact with all the three-receptor subtypes with SP preferring NK1, NKA preferring NK2 and NKB preferring NK3. This lack of specificity can be accounted for by the conformational flexibility of these short, linear peptides. Hence, identification of structural features of the agonists important for receptor binding and biological activity is of great significance in unraveling the molecular mechanisms involved in tachykinin receptor activation and also in rational design of novel therapeutic agents. Understanding structure of the ligand-receptor complex and analysis of topography of the binding pocket of the tachykinin receptor is also crucial in rational design of drugs.
这篇综述主要探讨了速激肽家族神经肽的结构特征的阐明，这些神经肽已知通过三种不同的 G 蛋白偶联受体亚型（即 NK1（神经激肽 1）、NK2（神经激肽 2）和 NK3（神经激肽 3）受体）相互作用。在哺乳动物中，速激肽已被证明能引发广泛的生理活动，如强力血管扩张、高血压作用和刺激血管外平滑肌，并且已知与多种临床情况有关，包括慢性疼痛、帕金森病、阿尔茨海默病、抑郁症、类风湿性关节炎、肠易激综合征和哮喘。速激肽的这种广谱作用归因于其对受体缺乏选择性。所有速激肽都与所有三种受体亚型相互作用，SP 优先与 NK1 结合，NKA 优先与 NK2 结合，NKB 优先与 NK3 结合。这种缺乏特异性可以归因于这些短线性肽的构象灵活性。因此，确定对受体结合和生物活性重要的激动剂的结构特征对于揭示速激肽受体激活涉及的分子机制以及合理设计新型治疗剂具有重要意义。了解配体-受体复合物的结构和分析速激肽受体的结合口袋的拓扑结构对于合理设计药物也至关重要。
