31 research outputs found
Chemogenomic Analysis of G-Protein Coupled Receptors and Their Ligands Deciphers Locks and Keys Governing Diverse Aspects of Signalling
Understanding the molecular mechanism of signalling in the important super-family of G-protein-coupled receptors (GPCRs) is causally related to questions of how and where these receptors can be activated or inhibited. In this context, it is of great interest to unravel the common molecular features of GPCRs as well as those related to an active or inactive state or to subtype specific G-protein coupling. In our underlying chemogenomics study, we analyse for the first time the statistical link between the properties of G-protein-coupled receptors and GPCR ligands. The technique of mutual information (MI) is able to reveal statistical inter-dependence between variations in amino acid residues on the one hand and variations in ligand molecular descriptors on the other. Although this MI analysis uses novel information that differs from the results of known site-directed mutagenesis studies or published GPCR crystal structures, the method is capable of identifying the well-known common ligand binding region of GPCRs between the upper part of the seven transmembrane helices and the second extracellular loop. The analysis shows amino acid positions that are sensitive to either stimulating (agonistic) or inhibitory (antagonistic) ligand effects or both. It appears that amino acid positions for antagonistic and agonistic effects are both concentrated around the extracellular region, but selective agonistic effects are cumulated between transmembrane helices (TMHs) 2, 3, and ECL2, while selective residues for antagonistic effects are located at the top of helices 5 and 6. Above all, the MI analysis provides detailed indications about amino acids located in the transmembrane region of these receptors that determine G-protein signalling pathway preferences
Structure of the human κ-opioid receptor in complex with JDTic
Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and—in the case of κ-opioid receptor (κ-OR)—dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5′-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure–activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR
Root-emitted volatile organic compounds: can they mediate belowground plant-plant interactions?
peer reviewedBackground
Aboveground, plants release volatile organic compounds (VOCs) that act as chemical
signals between neighbouring plants. It is now well documented that VOCs emitted by
the roots in the plant rhizosphere also play important ecological roles in the soil
ecosystem, notably in plant defence because they are involved in interactions between
plants, phytophagous pests and organisms of the third trophic level. The roles played
by root-emitted VOCs in between- and within-plant signalling, however, are still poorly
documented in the scientific literature.
Scope
Given that (1) plants release volatile cues mediating plant-plant interactions
aboveground, (2) roots can detect the chemical signals originating from their
neighbours, and (3) roots release VOCs involved in biotic interactions belowground,
the aim of this paper is to discuss the roles of VOCs in between- and within-plant
signalling belowground. We also highlight the technical challenges associated with the
analysis of root-emitted VOCs and the design of experiments targeting volatile-mediated
root-root interactions.
Conclusions
We conclude that root-root interactions mediated by volatile cues deserve more
research attention and that both the analytical tools and methods developed to study
the ecological roles played by VOCs in interplant signalling aboveground can be
adapted to focus on the roles played by root-emitted VOCs in between- and within-plant
signalling