Combining molecular dynamics (MD) in a hydrated phospholipid (DOPC) bilayer, a Monte Carlo search, and synthesis of locked nucleotide analogues, we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y(6) receptor. 2'-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than that for the corresponding flexible 2'-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583457 | PMC |
| http://dx.doi.org/10.1021/jm050911p | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Metal-organic framework-based nanoplatforms for synergistic anti-atherosclerosis therapy by regulating the PI3K/AKT/MSR1 pathway in macrophages.
Nanoscale
December 2024
Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Atherosclerosis is the main pathogenic factor of various cardiovascular diseases. During the pathogenesis of atherosclerosis, macrophages play a major role, mainly by secreting pro-inflammatory cytokines and taking in lipids to form foam cells. Thiamine pyrophosphate (TPP) is an antagonist of the P2Y6 receptor, which is overexpressed on macrophages during atherosclerosis and facilitates the lipid phagocytosis of macrophages.
View Article and Find Full Text PDFExtracellular ATP Release Triggered by I-Trastuzumab Mitigates Radiation-Induced Reduction in Cell Viability through the P2Y Receptor in SKOV3 Cells.
Biol Pharm Bull
November 2024
Department of Quantum-Applied Biosciences, Takasaki Institute for Advanced Quantum Science, National Institute for Quantum Science and Technology.
Intracellular ATP is released outside cells by various stimuli and is involved in cytoprotection by activating purinergic receptors. However, it remains unclear whether targeted radionuclide therapy induces extracellular ATP release. Here, we prepared I-labeled trastuzumab (I-trastuzumab) and examined extracellular ATP release and its roles in I-trastuzumab's growth inhibitory effects.
View Article and Find Full Text PDFP2Y12 receptor-mediated cyclooxygenase 2 (COX-2) expression enhances tumor cell progression in a mouse model of lymphoma.
Purinergic Signal
October 2024
Neuroinflammation Research Lab, Faculty of Life Sciences and Biotechnology, South Asian University, Rajpur Road, Maidan Garhi, New Delhi, 110068, India.
The pro-inflammatory enzyme cyclooxygenase 2 (COX-2) has been known to impart metastatic property to cancer cells. However, blocking of COX-2 with nonsteroidal anti-inflammatory drugs or COX-2-specific inhibitors has failed in clinical trials due to adverse effects associated with their prolonged use. We have previously shown that extracellular ATP (eATP), a major component of the tumor microenvironment, enhances COX-2 expression several-fold, both in macrophages and in various cancer cells, by acting on purinergic (P2) receptors.
View Article and Find Full Text PDFP2RY6 deletion promotes UVB-induced skin carcinogenesis by activating the PI3K/AKT signal pathway.
Cancer Sci
January 2025
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Our previous research has demonstrated that P2RY6 functions as an oncogene in DMBA/TPA-induced two-stage chemical skin carcinogenesis in mice. However, considering that human skin cancer is predominantly attributed to UV radiation from sunlight, additional investigations are needed to elucidate the role of P2RY6 in UVB-induced skin carcinogenesis. Surprisingly, we found that P2ry6-deficient mice exhibited marked promotion to UVB-induced skin papilloma formation compared with wild-type mice, suggesting its tumor-suppressive role in UVB-induced skin cancer.
View Article and Find Full Text PDFDiscovery of a potent, Highly selective, and In vivo anti-inflammatory Efficacious, P2YR antagonist with a novel quinoline-pyrazole scaffold.
Eur J Med Chem
December 2024
Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China. Electronic address:
The P2Y receptor (P2YR), as a crucial member of the purine family, is a potential therapeutic target for the treatment of intestinal inflammation, tracheal inflammation and diabetes. We first discovered the hit compound (5a, IC = 168.5 nM against P2YR) through our in-house library screening.
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!