Department of Pharmaceutical Sciences and Experimental Therapeutics College of Pharmacy, University of Iowa, 180 S Grand Avenue, CPB 538, Iowa City, IA 52245, USA.
Present address: Beckman Coulter, Indianapolis, IN 46268, USA.
Chembiochem. 2021 May 4;22(9):1609-1620. doi: 10.1002/cbic.202000740. Epub 2021 Feb 16.
Regulator of G protein signaling (RGS) proteins have attracted attention as a result of their primary role in directing the specificity as well as the temporal and spatial aspects of G protein-coupled receptor signaling. In addition, alterations in RGS protein expression have been observed in a number of disease states, including certain cancers. In this area, RGS17 is of particular interest. It has been demonstrated that, while RGS17 is expressed primarily in the central nervous system, it has been found to be inappropriately expressed in lung, prostate, breast, cervical, and hepatocellular carcinomas. Overexpression of RGS17 leads to dysfunction in inhibitory G protein signaling and an overproduction of the intracellular second messenger cAMP, which in turn alters the transcription patterns of proteins known to promote various cancer types. Suppressing RGS17 expression with RNA interference (RNAi) has been found to decrease tumorigenesis and sufficiently prevents cancer cell migration, leading to the hypothesis that pharmacological blocking of RGS17 function could be useful in anticancer therapies. We have identified small-molecule fragments capable of binding the RGS homology (RH) domain of RGS17 by using a nuclear magnetic resonance fragment-based screening approach. By chemical shift mapping of the two-dimensional N, H heteronuclear single quantum coherence (HSQC) spectra of the backbone-assigned N-labeled RGS17-RH, we determined the fragment binding sites to be distant from the Gα interface. Thus, our study identifies a putative fragment binding site on RGS17 that was previously unknown.
RGS（G 蛋白信号调节蛋白）蛋白因其在指导 G 蛋白偶联受体信号的特异性以及时间和空间方面的主要作用而受到关注。此外，在许多疾病状态中观察到 RGS 蛋白表达的改变，包括某些癌症。在这一领域，RGS17 尤为引人注目。已经证明，虽然 RGS17 主要在中枢神经系统中表达，但它在肺癌、前列腺癌、乳腺癌、宫颈癌和肝癌中被发现表达不当。RGS17 的过表达导致抑制性 G 蛋白信号转导功能障碍和细胞内第二信使 cAMP 的过度产生，这反过来又改变了已知促进各种癌症类型的蛋白质的转录模式。用 RNA 干扰（RNAi）抑制 RGS17 的表达已被发现可降低肿瘤发生并充分防止癌细胞迁移，从而提出了药理学阻断 RGS17 功能可能对癌症治疗有用的假说。我们通过使用核磁共振基于片段的筛选方法鉴定了能够结合 RGS17 的 RGS 同源（RH）结构域的小分子片段。通过对全骨架标记的 N 标记的 RGS17-RH 的二维 N、H 异核单量子相干（HSQC）谱的化学位移映射，我们确定了片段结合位点远离 Gα 界面。因此，我们的研究确定了 RGS17 上以前未知的假定片段结合位点。
