Enabling systemic identification and functionality profiling for Cdc42 homeostatic modulators

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
出处
期刊:Communications chemistry [Nature Portfolio]
卷期号:7 (1)
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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
2秒前
Rr完成签到,获得积分10
2秒前
脑洞疼应助555557采纳,获得10
4秒前
点到为止发布了新的文献求助10
4秒前
7秒前
啵噜噜噜啊完成签到,获得积分10
10秒前
OYY完成签到 ,获得积分10
10秒前
烂漫的断秋完成签到 ,获得积分10
11秒前
12秒前
12秒前
Lucas应助Livrik采纳,获得10
13秒前
cyn0762完成签到,获得积分10
13秒前
点到为止完成签到,获得积分10
14秒前
15秒前
Akim应助lll采纳,获得10
16秒前
高贵灵槐完成签到 ,获得积分10
17秒前
20秒前
wxh完成签到 ,获得积分20
20秒前
量子星尘发布了新的文献求助10
20秒前
liuzi发布了新的文献求助20
21秒前
雨过天晴完成签到,获得积分10
22秒前
花花完成签到 ,获得积分10
23秒前
24秒前
26秒前
汪汪发布了新的文献求助10
29秒前
29秒前
30秒前
33秒前
追寻筮关注了科研通微信公众号
33秒前
miaojuly发布了新的文献求助10
34秒前
充电宝应助汪汪采纳,获得10
35秒前
36秒前
涵哈哈哈哈哈完成签到 ,获得积分10
38秒前
40秒前
liuzi完成签到,获得积分10
40秒前
科目三应助油菜的星星采纳,获得10
42秒前
42秒前
42秒前
43秒前
43秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988868
求助须知:如何正确求助?哪些是违规求助? 3531255
关于积分的说明 11253071
捐赠科研通 3269858
什么是DOI,文献DOI怎么找? 1804822
邀请新用户注册赠送积分活动 881994
科研通“疑难数据库(出版商)”最低求助积分说明 809035