Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Curr Top Med Chem. 2013;13(1):55-63. doi: 10.2174/1568026611313010006.
The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131-143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor α. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics.
变构调节的模体模型引起了人们对蛋白质的关注，这些蛋白质可以作为功能上不同的组装体的平衡而存在，其中：一种亚基构象组装成一种多聚体；另一种亚基构象组装成另一种多聚体；并且各种多聚体处于动态平衡中，其位置可以通过结合到多聚体特异性配体结合位点的配体来调节。卟胆原合酶（PBGS）的案例研究说明了这种平衡如何为疾病机制、药物发现、了解药物副作用以及识别药物发现工作可能集中在四级结构动力学的蛋白质提供了教训。变构的模体模型已被提出适用于广泛的与疾病相关的蛋白质（Selwood，T.，Jaffe，E.，（2012）Arch。Bioch。Biophys，519:131-143）。本文讨论了与疾病相关的假定模体苯丙氨酸羟化酶、HIV 整合酶、丙酮酸激酶和肿瘤坏死因子α的药物发现的四级结构动力学方面。还强调了转甲状腺素蛋白的四级结构平衡以及集中控制其四级结构动力学的成功药物发现努力。
