Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Australia.
Biochem Pharmacol. 2010 Apr 15;79(8):1083-91. doi: 10.1016/j.bcp.2009.11.019. Epub 2009 Nov 30.
Monoamine transporters are a group of transmembrane neurotransmitter sodium symporter (NSS) transporters that play a crucial role in regulating biogenic monoamine concentrations at peripheral and central synapses. Given the key role played by serotonin, dopamine and noradrenaline in addictive and disease states, structure-function studies have been conducted to help guide the development of improved central nervous system therapeutics. Extensive pharmacological, immunological and biochemical studies, in conjunction with three-dimensional homology modeling, have been performed to structurally and functionally characterise the monoamine transporter substrate permeation pathway, substrate selectivity, and binding sites for ions, substrates and inhibitors at the molecular level. However, only recently has it been possible to start to construct an accurate molecular interaction network for the monoamine transporters and their corresponding substrates and inhibitors. Crystal structures of Aquifex aeolicus leucine transporter (LeuT(Aa)), a homologous protein to monoamine transporters that has been experimentally demonstrated to share similar structural folds with monoamine transporters, have been determined in complex with amino acids and inhibitors. The molecular interactions of leucine and tricyclic antidepressants (TCA) has supported many of the predictions based on the mutational studies. Models constructed from LeuT(Aa) are now allowing a rational approach to further clarify the molecular determinants of NSS transporter-ligand complexes, and potentially the ability to better manipulate drug specificity and affinity. In this review, we compare the structure-function relationships of other SLC6 NSS family transporters with monoamine transporters, and discuss possible mechanisms involved in substrate binding and transport, and modes of inhibition by TCAs.
单胺转运体是一组跨膜神经递质钠协同转运体（NSS），在调节外周和中枢突触中生物单胺浓度方面发挥着关键作用。鉴于 5-羟色胺、多巴胺和去甲肾上腺素在成瘾和疾病状态中的关键作用，已经进行了结构-功能研究，以帮助指导中枢神经系统治疗药物的开发。已经进行了广泛的药理学、免疫学和生物化学研究，结合三维同源建模，以在分子水平上对单胺转运体底物渗透途径、底物选择性以及离子、底物和抑制剂的结合位点进行结构和功能表征。然而，直到最近才有可能开始构建单胺转运体及其相应的底物和抑制剂的准确分子相互作用网络。已经确定了 Aquifex aeolicus 亮氨酸转运体（LeuT(Aa)）的晶体结构，LeuT(Aa)是与单胺转运体具有同源结构的蛋白质，已经通过实验证明与单胺转运体具有相似的结构折叠。已经确定了亮氨酸和三环抗抑郁药（TCA）与 LeuT(Aa)复合物的分子相互作用，这支持了许多基于突变研究的预测。现在，从 LeuT(Aa)构建的模型允许采用合理的方法进一步阐明 NSS 转运体-配体复合物的分子决定因素，并有可能更好地操纵药物特异性和亲和力。在这篇综述中，我们比较了其他 SLC6 NSS 家族转运体与单胺转运体的结构-功能关系，并讨论了底物结合和转运以及 TCA 抑制的可能机制。
