CDC42型
鸟嘌呤核苷酸交换因子
化学
G蛋白偶联受体
GTP酶
计算生物学
信号转导
细胞生物学
生物
药理学
作者
Satyaveni Malasala,Fereshteh Azimian,Yanhua Chen,Jeffery L. Twiss,Christi Boykin,Shayan Nik Akhtar,Qun Lu
标识
DOI:10.1038/s42004-024-01352-7
摘要
Maintaining body homeostasis is the ultimate key to health. There are rich resources of bioactive materials for the functionality of homeostatic modulators (HMs) from both natural and synthetic chemical repertories1–3. HMs are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction (e.g. Buspirone and benzodiazepines)4–7. However, the identification of therapeutic HMs are often unpredictable and limited to membrane protein receptors and ion channels. Based on a serendipitously encountered small molecule ZCL278 with partial agonist (PA) profile as a model compound8–10, the Mant-GTP fluorophore-based Cdc42-GEF (guanine nucleotide exchange factor) screening uncovered a near holistic spectrum of HMs for Cdc42, a cytoplasmic small GTPase in the Ras superfamily11,12. We categorized these HMs as functionally distinct, with some previously understudied classes: Class I-competitive PAs, Class II-hormetic agonists, Class III-bona fide inhibitors, Class IV-bona fide activators, and Class V-ligand-enhanced agonists. The model HMs elicited striking biological functionalities in modulating bradykinin activation of Cdc42 signaling as well as actin remodeling while they ameliorated Alzheimer's disease-like social behavior in mouse model. Furthermore, molecular structural modeling analyses led to the concept of preferential binding pocket order (PBPO) for profiling HMs that target Cdc42 complexed with intersectin (ITSN), a GEF selectively activating Cdc42. Remarkably, the PBPO enabled a prediction of HM class that mimics the pharmacological functionality. Therefore, our study highlights a model path to actively capture different classes of HM to broaden therapeutic landscape. Homeostatic modulators (HMs) are powerful modern therapeutics for human diseases including neuropsychiatric diseases, mental disorders, and drug addiction; however, their discovery is often unpredictable and limited to membrane protein receptors and ion channels. Here, the authors analyze a spectrum of novel HMs for Cdc42, a cytoplasmic small GTPase in the Ras superfamily, with striking biological functionalities and potential therapeutic applications.
科研通智能强力驱动
Strongly Powered by AbleSci AI