Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry.

G Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development.

Probe dependence and biased potentiation of metabotropic glutamate receptor 5 is mediated by differential ligand interactions in the common allosteric binding site.

The metabotropic glutamate receptor 5 (mGlu) is a promising therapeutic target for multiple CNS disorders. Recent mGlu drug discovery has focused on targeting binding sites within the mGlu 7-transmembrane domain (7TM) that are topographically distinct from that of the endogenous ligand. mGlu primarily couples to G proteins leading to mobilization of intracellular Ca (iCa), but also activates iCa independent signaling pathways, with biased agonism/modulation operative for multiple positive allosteric modulator (PAM) and PAM-agonist chemotypes.

Differential contribution of metabotropic glutamate receptor 5 common allosteric binding site residues to biased allosteric agonism.

Allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu) represent an attractive therapeutic strategy for multiple CNS disorders. Chemically distinct mGlu positive allosteric modulators (PAMs) that interact with a common binding site can demonstrate biased allosteric agonism relative to the orthosteric agonist, DHPG, when comparing activity in signaling assays such as IP accumulation, ERK1/2 phosphorylation (pERK1/2) and iCa mobilization. However, the structural basis for such biased agonism is not well understood.

Metabotropic glutamate receptor 5 (mGlu )-positive allosteric modulators differentially induce or potentiate desensitization of mGlu signaling in recombinant cells and neurons.

Allosteric modulators of metabotropic glutamate receptor 5 (mGlu ) are a promising therapeutic strategy for a number of neurological disorders. Multiple mGlu -positive allosteric modulator (PAM) chemotypes have been discovered that act as either pure PAMs or as PAM-agonists in recombinant and native cells. While these compounds have been tested in paradigms of receptor activation, their effects on receptor regulatory processes are largely unknown.

Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.

Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation.