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Orthosteric and Allosteric Binding Sites on GPCRs

Analysis of the calcitonin receptor ligand-binding interface

Understanding the molecular basis underlying interaction between receptors and their ligands is fundamental to understanding receptor specificity and activation. Traditional approaches to identify important interactions between the two include receptor mutagenesis or structural modification to the interacting ligand. In the case of the calcitonin receptor, the ligand is a peptide hormone of 32 amino acids and it interacts with receptors for which very little structural information is available. To gain a better understanding of the biomolecular interface between calcitonin and its receptor we have adopted a photoaffinity scanning approach to derive information about proximity of peptide ligand and receptor residues. This provides key information about the physical proximity of ligand and receptor amino acids, which is used to guide molecular modelling of ligand-receptor interactions and to help the interpretation of site-directed mutagenesis studies.

Allosteric modulators of muscarinic acetylcholine receptors

The muscarinic acetylcholine receptors (mAChRs) are an important family of GPCRs that mediate the majority of the actions of the neurotransmitter, acetylcholine (ACh), in both the central nervous system and the periphery. They are also a classic example of a lack of highly selective therapeutic agents because the orthosteric site for ACh is highly conserved across all five mAChR subtypes. However, we and others have shown that these receptors possess additional allosteric sites that can be selectively targeted by different ligands to modulate the pharmacology of compounds that act at the orthosteric site. We are currently investigating the effects of allosteric ligands on different members of the mAChR family, with a particular emphasis on delineating novel allosteric effects on signaling efficacy, desensitization and receptor regulation in addition to effects on neurotransmitter binding.

Mechanisms of action of allosteric modulators of adenosine A1 receptors

Adenosine A1 receptors are an important class of GPCR implicated in a number of conditions including cerebral and myocardial ischemia-reperfusion, neuropathic pain and seizure activity. However, given the wide distribution of these receptors throughout the body, A1 receptor orthosteric agonists are typically associated with a wide variety of side-effects. In contrast, selective allosteric enhancers of A1 receptors are predicted to provide a higher degree of spatial and temporal specificity in promoting the effects of endogenous adenosine where and when required. We have recently been focusing on the role of sulfhydryl groups on the A1 receptor as potential contributors to an allosteric binding pocket and/or as contributing to a key conformational change necessary for transmission of the allosteric effect. In collaboration with Prof. Peter J. Scammells (Dept. of Medicinal Chemistry, Victorian College of Pharmacy), we have also been investigating the effects of a novel series of A1 enhancers.