胺能受体的晶体结构能为我们设计亚型选择性配体提供哪些信息？
What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands?
作者信息
Michino Mayako, Beuming Thijs, Donthamsetti Prashant, Newman Amy Hauck, Javitch Jonathan A, Shi Lei
机构信息
Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.).
Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (M.M., L.S.); Schrödinger Inc., New York, New York (T.B.); Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (P.D., J.A.J.); and Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland (A.H.N.)
出版信息
Pharmacol Rev. 2015;67(1):198-213. doi: 10.1124/pr.114.009944.
G protein-coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype-selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy.
G蛋白偶联受体（GPCRs）是一类重要的药物靶点，属于整合膜蛋白。特别是，胺能GPCRs与目前市场上很大一部分药物相互作用。然而，大多数靶向这些受体的药物都伴有不良副作用，部分原因是与预期靶受体的密切同源物发生了混杂相互作用。在此，基于对目前所有37个胺能GPCRs高分辨率晶体结构的系统分析，我们综述了有助于设计亚型选择性化合物且可被利用的结构元件。我们描述了二级结合口袋（SBPs）的作用，以及配体进入正构结合位点的途径差异在决定选择性方面的作用。此外，利用现有的晶体结构，我们确定了与受体激活相关的SBPs构象变化，并探讨了这些变化对合理开发具有定制疗效的选择性配体的意义。
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