Kenakin Terry
GlaxoSmithKline Research and Development, Research Triangle Park, NC 27709, USA.
J Recept Signal Transduct Res. 2010 Oct;30(5):313-21. doi: 10.3109/10799893.2010.503964.
Seven transmembrane receptors (7TMRs) are proteins that convey signals through changes in conformation. These conformations are stabilized by external molecules (i.e. agonists, antagonists, modulators) and act upon other bodies (termed 'guests') which can be other molecules in the extracellular space, or proteins along the plane of the membrane (receptor oligomerization) or signaling proteins in the cytosol (i.e. G protein, β-arrestin). These elements comprise allosteric systems and a great deal of 7TMR pharmacology can be considered in terms of allosteric behavior. Allosteric ligands acting on 7TMRs possess four unique behaviors that can be valuable therapeutically; (1) the ability to alter the interaction of very large proteins, (2) probe dependence, (3) saturable effect, and (4) induction of separate changes in affinity and efficacy of other ligands. Two of these behaviors (namely probe dependence for CCR5-based HIV-1 entry inhibitors and functional selectivity for biased agonism) will be highlighted with examples.
七跨膜受体（7TMRs）是一类通过构象变化传递信号的蛋白质。这些构象由外部分子（即激动剂、拮抗剂、调节剂）稳定，并作用于其他实体（称为“客体”），这些客体可以是细胞外空间中的其他分子、膜平面上的蛋白质（受体寡聚化）或胞质溶胶中的信号蛋白（即G蛋白、β-抑制蛋白）。这些元件构成变构系统，许多7TMR药理学可以从变构行为的角度来考虑。作用于7TMRs的变构配体具有四种独特的行为，在治疗上可能具有价值；（1）改变非常大的蛋白质相互作用的能力，（2）探针依赖性，（3）饱和效应，以及（4）诱导其他配体的亲和力和效力发生单独变化。将通过实例重点介绍其中两种行为（即基于CCR5的HIV-1进入抑制剂的探针依赖性和偏向激动作用的功能选择性）。
