Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A adenosine receptor (AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics. All six tryptophan indole and eight glycine backbone N-H NMR signals in AAR were individually assigned. These NMR probes provided insight into the role of Asp52 as an allosteric link between the orthosteric drug binding site and the intracellular signaling surface, revealing strong interactions with the toggle switch Trp 246, and delineated the structural response to variable efficacy of bound drugs across AAR. The present data support GPCR signaling based on dynamic interactions between two semi-independent subdomains connected by an allosteric switch at Asp52.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766378 | PMC |
| http://dx.doi.org/10.1016/j.cell.2017.12.004 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Integrated Network Pharmacology and Metabolomics to Investigate the Effects and Possible Mechanisms of Ginsenoside Rg Glycine Ester Derivative Against Hypoxia.
Biomed Chromatogr
February 2025
School of Pharmaceutical Sciences, Jilin University, Changchun, People's Republic of China.
Previous studies have suggested that ginsenoside Rg glycine ester derivative (RG) exhibits therapeutic potential in mitigating hypoxia. This study aimed to elucidate the potential mechanism of RG in hypoxia injury through a combined approach of metabolomics and network pharmacology. Initially, a CoCl-induced cell hypoxia model was established, and the therapeutic impact of RG on biochemical indices was evaluated.
View Article and Find Full Text PDFLC-MS/MS Analyzing Praziquantel and 4-Hydroxypraziquantel Enantiomers in Black Goat Plasma and Mechanism of Stereoselective Pharmacokinetics.
Biomed Chromatogr
February 2025
Guangdong Provincial key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou, China.
Praziquantel (PZQ) is the most effective treatment for schistosomiasis, commonly administered as a racemic mixture of the two enantiomers. Despite many reports on the pharmacokinetics of PZQ, the stereoselective pharmacokinetics of PZQ and its major metabolite 4-hydroxypraziquantel (4-OH-PZQ) remain poorly understood in goats. In this study, the chiral LC-MS/MS method was further optimized for separating and quantifying PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ and their enantiomers and then applied for the molecular pharmacokinetics of three analytes in black goat plasma.
View Article and Find Full Text PDFFrom Antipsychotic to Neuroprotective: Computational Repurposing of Fluspirilene as a Potential PDE5 Inhibitor for Alzheimer's Disease.
J Comput Chem
January 2025
Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, New South Wales, Australia.
Phosphodiesterase 5 (PDE5) inhibitors have shown great potential in treating Alzheimer's disease by improving memory and cognitive function. In this study, we evaluated fluspirilene, a drug commonly used to treat schizophrenia, as a potential PDE5 inhibitor using computational methods. Molecular docking revealed that fluspirilene binds strongly to PDE5, supported by hydrophobic and aromatic interactions.
View Article and Find Full Text PDFNew Insights Into Hepatic Impairment (HI) Trials.
Clin Transl Sci
January 2025
Clinical Pharmacology, Translational Medicine and Clinical Pharmacology, Boehringer-Ingelheim Pharma, Ingelheim, Germany.
Hepatic impairment (HI) trials are traditionally part of the clinical pharmacology development to assess the need for dose adaptation in people with impaired metabolic capacity due to their diseased liver. This review aimed at looking into the data from dedicated HI studies, cluster these data into various categories and connect the effect by HI with reported pharmacokinetics (PK) properties in order to identify patterns that may allow waiver, extrapolations, or adapted HI study designs. Based on a ratio ≥ 2 or ≤ 0.
View Article and Find Full Text PDFInvestigation of Thiazolidine-2,4-Dione Derivatives as Acetylcholinesterase Inhibitors: Synthesis, In Vitro Biological Activities and In Silico Studies.
ChemistryOpen
January 2025
Department of Chemistry, Faculty of Sciences, University of Guilan, Rasht, 4193833697, Iran.
The inhibition of acetylcholinesterase (AChE), an enzyme responsible for the inactivation and decrease in acetylcholine in the cholinergic pathway, has been considered an attractive target for small-molecule drug discovery in Alzheimer's disease (AD) therapy. In the present study, a series of TZD derivatives were designed, synthesized, and studied for drug likeness, blood-brain barrier (BBB) permeability, and adsorption, distribution, metabolism, excretion, and toxicity (ADMET). Additionally, docking studies of the designed compounds were performed on AChE.
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!