Departments of Biological Sciences and of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
Departments of Biological Sciences and of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, USA.
J Biol Chem. 2022 Sep;298(9):102279. doi: 10.1016/j.jbc.2022.102279. Epub 2022 Jul 19.
G protein-coupled receptor (GPCR) kinases (GRKs) and arrestins interact with agonist-bound GPCRs to promote receptor desensitization and downregulation. They also trigger signaling cascades distinct from those of heterotrimeric G proteins. Biased agonists for GPCRs that favor either heterotrimeric G protein or GRK/arrestin signaling are of profound pharmacological interest because they could usher in a new generation of drugs with greatly reduced side effects. One mechanism by which biased agonism might occur is by stabilizing receptor conformations that preferentially bind to GRKs and/or arrestins. In this review, we explore this idea by comparing structures of GPCRs bound to heterotrimeric G proteins with those of the same GPCRs in complex with arrestins and GRKs. The arrestin and GRK complexes all exhibit high conformational heterogeneity, which is likely a consequence of their unusual ability to adapt and bind to hundreds of different GPCRs. This dynamic behavior, along with the experimental tactics required to stabilize GPCR complexes for biophysical analysis, confounds these comparisons, but some possible molecular mechanisms of bias are beginning to emerge. We also examine if and how the recent structures advance our understanding of how arrestins parse the "phosphorylation barcodes" installed in the intracellular loops and tails of GPCRs by GRKs. In the future, structural analyses of arrestins in complex with intact receptors that have well-defined native phosphorylation barcodes, such as those installed by the two nonvisual subfamilies of GRKs, will be particularly illuminating.
G 蛋白偶联受体 (GPCR) 激酶 (GRKs) 和 arrestin 与激动剂结合的 GPCR 相互作用，促进受体脱敏和下调。它们还触发与异三聚体 G 蛋白不同的信号级联。对 GPCR 的偏性激动剂，无论是偏向异三聚体 G 蛋白还是偏向 GRK/arrestin 信号的激动剂，都具有深远的药理学意义，因为它们可能开创新一代副作用大大降低的药物。偏性激动可能发生的一种机制是通过稳定受体构象，这些构象优先与 GRKs 和/或 arrestin 结合。在这篇综述中，我们通过比较与异三聚体 G 蛋白结合的 GPCR 结构与与 arrestin 和 GRK 结合的相同 GPCR 结构来探讨这个想法。arrestin 和 GRK 复合物都表现出高度的构象异质性，这可能是它们适应和结合数百种不同 GPCR 的异常能力的结果。这种动态行为，以及为生物物理分析稳定 GPCR 复合物所需的实验策略，使这些比较变得复杂，但一些偏性的可能分子机制开始显现。我们还研究了最近的结构是否以及如何增进我们对 arrestin 如何解析 GRKs 在 GPCR 的细胞内环和尾部上安装的“磷酸化条码”的理解。在未来，对与具有明确天然磷酸化条码的完整受体结合的 arrestin 的结构分析，例如由两个非视觉 GRK 亚家族安装的条码，将特别有启发性。
