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Christopoulos A.,Monash Institute of Pharmaceutical Sciences
Molecular Pharmacology

It is now widely accepted that G protein-coupled receptors (GPCRs) are highly dynamic proteins that adopt multiple active states linked to distinct functional outcomes. Furthermore, these states can be differentially stabilized not only by orthosteric ligands but also by allosteric ligands acting at spatially distinct binding sites. The key pharmacologic characteristics of GPCR allostery include improved selectivity due to either greater sequence divergence between receptor subtypes and/or subtype-selective cooperativity, a ceiling level to the effect, probe dependence (whereby the magnitude and direction of the allosteric effect change with the nature of the interacting ligands), and the potential for biased signaling. Recent chemical biology developments are beginning to demonstrate how the incorporation of analytical pharmacology and operational modeling into the experimental workflow can enrich structure-activity studies of allostery and bias, and have also led to the discovery of a new class of hybrid orthosteric/ allosteric (bitopic) molecules. The potential for endogenous allosteric modulators to play a role in physiology and disease remains to be fully appreciated but will likely represent an important area for future studies. Finally, breakthroughs in structural and computational biology are beginning to unravel the mechanistic basis of GPCR allosteric modulation at the molecular level. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics. Source

Galea C.A.,Monash Institute of Pharmaceutical Sciences
Cellular and molecular life sciences : CMLS

MMP23 is a member of the matrix metalloprotease family of zinc- and calcium-dependent endopeptidases, which are involved in a wide variety of cellular functions. Its catalytic domain displays a high degree of structural homology with those of other metalloproteases, but its atypical domain architecture suggests that it may possess unique functional properties. The N-terminal MMP23 pro-domain contains a type-II transmembrane domain that anchors the protein to the plasma membrane and lacks the cysteine-switch motif that is required to maintain other MMPs in a latent state during passage to the cell surface. Instead of the C-terminal hemopexin domain common to other MMPs, MMP23 contains a small toxin-like domain (TxD) and an immunoglobulin-like cell adhesion molecule (IgCAM) domain. The MMP23 pro-domain can trap Kv1.3 but not closely-related Kv1.2 channels in the endoplasmic reticulum, preventing their passage to the cell surface, while the TxD can bind to the channel pore and block the passage of potassium ions. The MMP23 C-terminal IgCAM domain displays some similarity to Ig-like C2-type domains found in IgCAMs of the immunoglobulin superfamily, which are known to mediate protein-protein and protein-lipid interactions. MMP23 and Kv1.3 are co-expressed in a variety of tissues and together are implicated in diseases including cancer and inflammatory disorders. Further studies are required to elucidate the mechanism of action of this unique member of the MMP family. Source

Irving H.R.,Monash Institute of Pharmaceutical Sciences
Plant signaling & behavior

Guanylate cyclase (GC) catalyzes the formation of cGMP and it is only recently that such enzymes have been characterized in plants. One family of plant GCs contains the GC catalytic center encapsulated within the intracellular kinase domain of leucine rich repeat receptor like kinases such as the phytosulfokine and brassinosteroid receptors. In vitro studies show that both the kinase and GC domain have catalytic activity indicating that these kinase-GCs are examples of moonlighting proteins with dual catalytic function. The natural ligands for both receptors increase intracellular cGMP levels in isolated mesophyll protoplast assays suggesting that the GC activity is functionally relevant. cGMP production may have an autoregulatory role on receptor kinase activity and / or contribute to downstream cell expansion responses. We postulate that the receptors are members of a novel class of receptor kinases that contain functional moonlighting GC domains essential for complex signaling roles. Source

Canals M.,Monash Institute of Pharmaceutical Sciences
Molecular Pharmacology

This Commentary focuses on two articles in the October 2015 issue of Molecular Pharmacology that investigate the role of μ-opioid receptor phosphorylation in receptor agonist binding and desensitization. The work of Birdsong et al. and Yousuf et al. clearly highlights the complexity that researchers face when trying to assess the signaling and regulatory consequences of G protein-coupled receptor phosphorylation. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Source

Le T.,CSIRO | Epa V.C.,CSIRO | Burden F.R.,CSIRO | Winkler D.A.,CSIRO | Winkler D.A.,Monash Institute of Pharmaceutical Sciences
Chemical Reviews

A study was conducted to demonstrate the most commonly used predictive quantitative structure-property relationship (QSPR) modeling methods and their applications to materials design. QSPR methods were based on the hypothesis that changes in molecular structure were reflected in changes in observed macroscopic properties of materials. QSPR modeling was a supervised learning method that extracted the complex relationships between the microscopic structure and properties of materials and their macroscopic properties. The key requirement for QSPR modeling was a reliable data set of molecules or materials whose microscopic structures and properties were well-defined along with their measured macroscopic properties of interest. The reliability of the experimental property chosen to be modeled was important, as it was one of the factors that determined the stability and predictivity of models. Source

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