KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a "quasi-triad plane" that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9556435 | PMC |
| http://dx.doi.org/10.1038/s41467-022-33761-4 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The bitter flavor of Banxia Xiexin decoction activates TAS2R38 to ameliorate low-grade inflammation in the duodenum of mice with functional dyspepsia.
J Ethnopharmacol
December 2024
Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210008, China. Electronic address:
Ethnopharmacological Relevance: Banxia Xiexin Decoction (BXD) is a traditional herbal formulation with a bitter flavor that has a long-standing history of use in Asia for treating functional dyspepsia (FD). In traditional Chinese medicine, the bitter flavor is believed to play a critical role in the therapeutic activity of BXD. The ethnopharmacological properties of bitter plant extracts are closely associated with their anti-inflammatory effects, which may contribute to their efficacy in FD.
View Article and Find Full Text PDFCoptisine acts as a nucleolus fluorescent probe in vitro.
Biochem Biophys Res Commun
January 2025
Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, China; Kaifeng Key Lab for Cataract and Myopia, Institute of Eye Disease, Kaifeng Central Hospital, Kaifeng, China. Electronic address:
Coptisine (COP) is a natural protoberberine isoquinoline alkaloid that is isolated from Coptis chinensis and exhibits a variety of pharmacological activities, such as the inhibition of tumor growth, bacterial infection, inflammation and oxidative stress. In this study, COP penetrated and produced fluorescent signals in living tumor cell lines, primary MEF cells and polyformaldehyde-fixed cells. The fluorescent signal was detected at a wavelength of 488 nm.
View Article and Find Full Text PDFHPLC Fingerprint Combined With Chemometrics and Multicomponent Content Determination for Quality Evaluation and Control of Huangma Tincture.
Phytochem Anal
December 2024
Preparation Center, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China.
Introduction: Huangma Tincture (HMT) is a Chinese patent medicine with a history of clinical use for more than 60 years, widely used for treating dermal chronic ulcer such as diabetic foot ulcer. However, the overall quality evaluation and control method of HMT has not yet been researched.
Objective: The aim of this study is to establish a comprehensive quality evaluation and control method for HMT based on high-performance liquid chromatography (HPLC) fingerprint, chemometrics, and multicomponent content determination.
Study on the correlation between alkaloids and tastes of Rhizome from four species based on UHPLC-QQQ-MS/MS combined with electronic tongue technique.
Front Plant Sci
November 2024
Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China.
Article Synopsis
- The study aims to improve the objectivity of taste evaluation for rhizome (CR) by linking its taste properties to alkaloid content, moving away from traditional subjective assessments.
- Researchers used advanced techniques like UHPLC-QQQ-MS/MS and an electronic tongue to analyze ten alkaloids and eight tastes, identifying key compounds like jatrorrhizine and berberrubine that influence taste perceptions.
- Findings highlight that bitterness correlates with specific alkaloids, suggesting that aftertaste and astringency are potential indicators for evaluating the quality of CR.
Cyanuric chloride-modified dendritic SiO nanoparticle for switch-on fluorescence monitoring and dispersive solid-phase extraction of isoquinoline alkaloids.
J Chromatogr A
January 2025
Department of Pharmacy, School of Biomedical and Pharmaceutical Sciences, Shaanxi University of Science & Technology, Xi'an 710021, China. Electronic address:
The determination of isoquinoline alkaloids (IQAs) is crucial for maximizing the pharmacological benefits of Rhizoma coptidis (RC). In this study, the dendritic silica sphere (dSiO) was covalently modified with cyanuric chloride (CNCl) to synthesize a porous dNSiO-CNCl NP. The fluorescence of berberine (Ber), palmatine (Pal), coptisine (Cop), and jatrorrhizine (Jat) was remarkably enhanced by dNSiO-CNCl NP for at least 38-fold, inspiring the accurate determination of the isoquinoline total alkaloids (IQTAs) in RC using fluorometry.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!