60 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
The History, Relevance, and Applications of the Periodic System in Geochemistry
Geochemistry is a discipline in the earth sciences concerned with understanding the chemistry of the Earth and what that chemistry tells us about the processes that control the formation and evolution of Earth materials and the planet itself. The periodic table and the periodic system, as developed by Mendeleev and others in the nineteenth century, are as important in geochemistry as in other areas of chemistry. In fact, systemisation of the myriad of observations that geochemists make is perhaps even more important in this branch of chemistry, given the huge variability in the nature of Earth materials – from the Fe-rich core, through the silicate-dominated mantle and crust, to the volatile-rich ocean and atmosphere. This systemisation started in the eighteenth century, when geochemistry did not yet exist as a separate pursuit in itself. Mineralogy, one of the disciplines that eventually became geochemistry, was central to the discovery of the elements, and nineteenth-century mineralogists played a key role in this endeavour. Early “geochemists” continued this systemisation effort into the twentieth century, particularly highlighted in the career of V.M. Goldschmidt. The focus of the modern discipline of geochemistry has moved well beyond classification, in order to invert the information held in the properties of elements across the periodic table and their distribution across Earth and planetary materials, to learn about the physicochemical processes that shaped the Earth and other planets, on all scales. We illustrate this approach with key examples, those rooted in the patterns inherent in the periodic law as well as those that exploit concepts that only became familiar after Mendeleev, such as stable and radiogenic isotopes
An anti-TNF--α antibody mimetic to treat ocular inflammation
Infliximab is an antibody that neutralizes TNF-α and is used principally by
systemic administration to treat many inflammatory disorders. We prepared the
antibody mimetic Fab-PEG-Fab (FpFinfliximab) for direct intravitreal injection to
assess whether such formulations have biological activity and potential utility for
ocular use. FpFinfliximab was designed to address side effects caused by antibody
degradation and the presence of the Fc region. Surface plasmon resonance
analysis indicated that infliximab and FpFinfliximab maintained binding affinity for
both human and murine recombinant TNF-α. No Fc mediated RPE cellular
uptake was observed for FpFinfliximab. Both Infliximab and FpFinfliximab suppressed
ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU
mice model after a single intravitreal injection at the onset of peak disease.
These results offer an opportunity to develop and formulate for ocular use, FpF
molecules designed for single and potentially multiple targets using bi-specific
FpFs
Pigment Synthesis for the Exploration of Binding Media Using a Lead-Free Alternative to Chrome Yellow
The sugars in the root of the cultivated carrot (cultivar Nantaise demi-longue) seasonal and climatological variations, distributions in the tissues, alterations during stockage
Fat cell .beta.1-adrenergic receptor: structural evidence for existence of disulfide bridges essential for ligand binding
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