The Open Question of How GPCRs Interact with GPCR Kinases (GRKs).
The Open Question of How GPCRs Interact with GPCR Kinases (GRKs).
复制标题
DOI：
10.3390/biom11030447
复制
发表时间：
2021-03-17
期刊：
影响因子：
5.5
通讯作者：
Tesmer JJG
中科院分区：
文献类型：
--
作者：
Cato MC;Yen YC;Francis CJ;Elkins KE;Shareef A;Sterne-Marr R;Tesmer JJG
G蛋白偶联受体（GPCR），调节大量的真核生物过程，是脱敏的各种机制，但最重要的是，通过GPCR激酶（GRKs）。自从GRK首次被发现以来，研究人员一直试图确定GRK的哪些结构特征用于选择GPCR的激动剂结合状态，以及这种结合事件如何反过来增强GRK催化活性。尽管从GRK的高分辨率晶体结构中获得了丰富的分子信息，但驱动激活的机制仍然难以捉摸，部分原因是GRK N-末端和活性位点系链区（先前提出作为受体对接位点并成为激酶结构域闭合的关键）通常是无序的或采用不一致的构象。然而，最近的两项研究表明GRKs的其他区域参与了与活性GPCR的直接相互作用。GPCR-GRK复合物的原子分辨率结构将有助于完善这些模型，但到目前为止，缺乏。在这里，我们评估了三种不同的模型GRKs如何识别激活的GPCR，讨论了用于生成它们的方法的局限性，然后通过实验测试了两个最新模型所建议的GRK 2中的假设GPCR相互作用位点。
G protein-coupled receptors (GPCRs), which regulate a vast number of eukaryotic processes, are desensitized by various mechanisms but, most importantly, by the GPCR kinases (GRKs). Ever since GRKs were first identified, investigators have sought to determine which structural features of GRKs are used to select for the agonist-bound states of GPCRs and how this binding event in turn enhances GRK catalytic activity. Despite a wealth of molecular information from high-resolution crystal structures of GRKs, the mechanisms driving activation have remained elusive, in part because the GRK N-terminus and active site tether region, previously proposed to serve as a receptor docking site and to be key to kinase domain closure, are often disordered or adopt inconsistent conformations. However, two recent studies have implicated other regions of GRKs as being involved in direct interactions with active GPCRs. Atomic resolution structures of GPCR–GRK complexes would help refine these models but are, so far, lacking. Here, we assess three distinct models for how GRKs recognize activated GPCRs, discuss limitations in the approaches used to generate them, and then experimentally test a hypothetical GPCR interaction site in GRK2 suggested by the two newest models.
登录
查看更多内容
影响因子：
7.5
作者：
Homan, Kristoff T.;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
影响因子：
4.8
作者：
Homan, Kristoff T.;Waldschmidt, Helen V.;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
影响因子：
4.8
作者：
Ballesteros, JA;Jensen, AD;Javitch, JA
通讯作者：
Javitch, JA
影响因子：
4
作者：
Homan, Kristoff T.;Larimore, Kelly M.;Elkins, Jonathan M.;Szklarz, Marta;Knapp, Stefan;Tesmer, John J. G.
通讯作者：
Tesmer, John J. G.
影响因子：
4.8
作者：
Allen, Samantha J.;Parthasarathy, Gopal;Lumb, Kevin J.
通讯作者：
Lumb, Kevin J.