Scholarlink

<p>G protein-coupled receptor kinase 2 (GRK2) is a key player in signal transduction and contains an N-terminus, a kinase domain (KD) and a C-terminus. Changes in the configuration of GRK2 regulate its allosteric effects, including KD closure and protein binding, and the interaction between the KD and the pleckstrin homology (PH) domain modulates the kinase activity of GRK2. GRK2 functions as a central molecule within a complex interactome, interacting with various cytoplasmic or membrane proteins in addition to G-protein coupled receptors (GPCRs), and plays a significant role in several GRK2 dysfunction-related diseases, including arthritis and cardiovascular disorders. Recently, GRK2 inhibitors—including peptide-based inhibitors, RNA aptamers, and small-molecule compounds—have been developed on the basis of targeted blockade of the GRK2–Gαq interface, GRK2–Gβγ interaction, and GRK2 KD–substrate binding, offering hope for the treatment of GRK2 dysfunction-related diseases. However, owing to the unfavourable properties of some small-molecule inhibitors and rapid degradation of peptides, the entry of these GRK2 inhibitors into clinical trials is limited. Understanding the regulation, activity, levels, or specific interactions of GRK2 is crucial for overcoming these challenges and optimizing the clinical use of GRK2 inhibitors. Our current review discusses the structure and function of GRK2, the research progress on GRK2 inhibitors and the regulatory role of GRK2 inhibitors in GRK2 dysfunction-related diseases to provide a significant theoretical basis for extensive research on GRK2-targeted therapies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月7日

查看全文
  • Chen-chen Han,
  • Hao-zhou Guo,
  • Fu-yuan Guo,
  • Hong-zheng Tan,
  • Hua-zhan Sun,
  • Jin-tao Gu,
  • Shu-jun Zuo,
  • Wei-kang Wang,
  • Yang Ma,
  • Wei Wei

摘要

G protein-coupled receptor kinase 2 (GRK2) is a key player in signal transduction and contains an N-terminus, a kinase domain (KD) and a C-terminus. Changes in the configuration of GRK2 regulate its allosteric effects, including KD closure and protein binding, and the interaction between the KD and the pleckstrin homology (PH) domain modulates the kinase activity of GRK2. GRK2 functions as a central molecule within a complex interactome, interacting with various cytoplasmic or membrane proteins in addition to G-protein coupled receptors (GPCRs), and plays a significant role in several GRK2 dysfunction-related diseases, including arthritis and cardiovascular disorders. Recently, GRK2 inhibitors—including peptide-based inhibitors, RNA aptamers, and small-molecule compounds—have been developed on the basis of targeted blockade of the GRK2–Gαq interface, GRK2–Gβγ interaction, and GRK2 KD–substrate binding, offering hope for the treatment of GRK2 dysfunction-related diseases. However, owing to the unfavourable properties of some small-molecule inhibitors and rapid degradation of peptides, the entry of these GRK2 inhibitors into clinical trials is limited. Understanding the regulation, activity, levels, or specific interactions of GRK2 is crucial for overcoming these challenges and optimizing the clinical use of GRK2 inhibitors. Our current review discusses the structure and function of GRK2, the research progress on GRK2 inhibitors and the regulatory role of GRK2 inhibitors in GRK2 dysfunction-related diseases to provide a significant theoretical basis for extensive research on GRK2-targeted therapies.