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G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking.
View Article and Find Full Text PDFExploring TAS2R46 biomechanics through molecular dynamics and network analysis.
Front Mol Biosci
December 2024
PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy.
Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food.
View Article and Find Full Text PDFStructural insights into endogenous ligand selectivity and activation mechanisms of FFAR1 and FFAR2.
Cell Rep
December 2024
State Key Laboratory of Drug Research, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310020, China. Electronic address:
Free fatty acid receptors (FFARs) play critical roles in metabolic regulation and are potential therapeutic targets for metabolic and inflammatory diseases. A comprehensive understanding of the activation mechanisms and endogenous ligand selectivity of FFARs is essential for drug discovery. Here, we report two cryoelectron microscopy structures of the human FFAR1 bound to the endogenous ligand docosahexaenoic acid (DHA) and G protein as well as FFAR2 in complex with butyrate and G at 3.
View Article and Find Full Text PDFExploring Bias in GPCR Signaling and its Implication in Drug Development: A One-Sided Affair.
Biochemistry
November 2024
Department of Biosciences and Bioengineering, Indian Institute of Technology Jammu, Jammu, Jammu and Kashmir 181221, India.
G protein-coupled receptors (GPCRs) play a pivotal role in regulating numerous physiological processes through their interactions with two key effectors: G proteins and β-arrestins (βarrs). This makes them crucial targets for therapeutic drug development. Interestingly, the evolving concept of biased signaling where ligands selectively activate either the G proteins or the βarrs has not only refined our understanding of segregation of physiological responses downstream of GPCRs but has also revolutionized drug discovery, offering the potential for treatments with enhanced efficacy and minimal side effects.
View Article and Find Full Text PDFDesign of allosteric modulators that change GPCR G protein subtype selectivity.
bioRxiv
November 2024
Department of Pharmacology, University of Minnesota Twin Cities, Minneapolis, MN, USA.
G protein-coupled receptors (GPCRs), the largest family of drug targets, can signal through 16 subtypes of Gα proteins. Biased compounds that selectively activate therapy-relevant pathways promise to be safer, more effective medications. The determinants of bias are poorly understood, however, and rationally-designed, G protein-subtype-selective compounds are lacking.
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