Identification of Potential Modulators of the RGS7/Gβ5/R7BP Complex.
Identification of Potential Modulators of the RGS7/Gβ5/R7BP Complex.
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DOI：
10.1177/24725552211020679
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Martemyanov KA
中科院分区：
文献类型：
--
作者：
Stoveken HM;Fernandez-Vega V;Muntean BS;Patil DN;Shumate J;Bannister TD;Scampavia L;Spicer TP;Martemyanov KA
G蛋白信号转导调节蛋白(RGS)蛋白作为关键的调节节点，通过G蛋白偶联受体(GPCRs)限制信号的寿命和范围。以前，药物抑制RGS活性的方法主要集中在通过阻断RGS蛋白与其调节的G蛋白之间的相互作用来抑制GTPase活性。然而，一些RGS蛋白也受结合伙伴的联合调节。一个值得注意的例子是哺乳动物的RGS7蛋白，它在代谢控制、视觉、奖励和阿片类镇痛剂的作用中具有突出的作用。在体内，RGS7与控制其稳定性和活性的结合伙伴5G蛋白β亚单位(Gβ5)和R7结合蛋白(R7BP)形成复合体。靶向整个RGS7/Gβ5/R7BP蛋白复合体提供了在阿片类药物参与后变构调节阿片受体信号的机会，同时潜在地绕过了不良副作用。因此，我们实施了一种新的策略来靶向RGS7/Gβ5和R7BP之间的相互作用。为此，我们使用基于tr-fret的高通量筛选试验来搜索蛋白质复合体抑制剂，该方法测量RGS7/Gβ5和R7BP之间的FRET信号的化合物介导的变化。我们进行了两次HTS活动，每次都从斯克里普斯药物发现库中筛选出约100,000种化合物。每一次筛选产生100多种抑制剂，将在此进行描述。
Regulators of G protein signaling (RGS) proteins serve as critical regulatory nodes to limit the lifetime and extent of signaling via G protein-coupled receptors (GPCRs). Previously, approaches to pharmacologically inhibit RGS activity have mostly focused on inhibition of GTPase activity by interrupting interaction of RGS proteins with the G proteins they regulate. However, several RGS proteins are also regulated by association with binding partners. A notable example is the mammalian RGS7 protein, which has prominent roles in metabolic control, vision, reward, and actions of opioid analgesics. In vivo, RGS7 exists in complex with the binding partners type 5 G protein β subunit (Gβ5) and R7 Binding Protein (R7BP) that control its stability and activity, respectively. Targeting the whole RGS7/Gβ5/R7BP protein complex affords the opportunity to allosterically tune opioid receptor signaling following opioid engagement while potentially bypassing undesirable side effects. Hence, we implemented a novel strategy to pharmacologically target the interaction between RGS7/Gβ5 and R7BP. To do so we searched for protein complex inhibitors using a TR-FRET-based high throughput screening (HTS) assay that measures compound-mediated alterations in the FRET signal between RGS7/Gβ5 and R7BP. We performed two HTS campaigns each screening ~100,000 compounds from the Scripps Drug Discovery Library. Each screen yielded over 100 inhibitors which will be described herein.
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Martemyanov, Kirill A.
DOI：
10.1073/pnas.0801508105
发表时间：
2008-04-29
影响因子：
11.1
作者：
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通讯作者：
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