Cromer Brett A, Morton Craig J, Parker Michael W
Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
Trends Biochem Sci. 2002 Jun;27(6):280-7. doi: 10.1016/s0968-0004(02)02092-3.
The GABA(A) receptor is the primary mediator of inhibitory neurotransmission in the brain and is a major target for neuromodulatory drugs such as benzodiazepines, barbiturates, ethanol and anaesthetics. However, our understanding of the molecular details of this receptor has been limited by a lack of high-resolution structural information. This article presents a new model for the extracellular, ligand-binding domain of the GABA(A) receptor, that is based on the recently determined structure of a soluble acetylcholine-binding protein. The model puts existing mutational and biochemical data into a three-dimensional context, shows details of the GABA- and benzodiazepine-binding sites, and highlights the importance of other regions in allosteric conformational change. This provides a new perspective on existing data and an exciting new framework for understanding this important family of receptors.
GABA(A)受体是大脑中抑制性神经传递的主要介质,也是苯二氮䓬类、巴比妥类、乙醇和麻醉剂等神经调节药物的主要作用靶点。然而,由于缺乏高分辨率的结构信息,我们对该受体分子细节的了解一直有限。本文基于最近确定的可溶性乙酰胆碱结合蛋白的结构,提出了一种GABA(A)受体细胞外配体结合结构域的新模型。该模型将现有的突变和生化数据置于三维背景中,展示了GABA和苯二氮䓬结合位点的细节,并突出了其他区域在变构构象变化中的重要性。这为现有数据提供了新的视角,也为理解这一重要的受体家族提供了一个令人兴奋的新框架。