The Cholecystokinin Type 1 (CCK-1R) receptor is a clinically relevant drug target for the treatment of obesity. CCK-1R is activated by the gut-brain peptide Cholecystokinin (CCK). CCK is secreted by the duodenum upon food entry where it exists in the surrounding tissue for up to 8 minutes. Activation of CCK-1R on vagal afferent nerves triggers the cessation of hunger. Prior approaches to targeting CCK-1R for appetite modification developed long-acting agonists to recreate CCK-induced signalling events. Despite significant interest and five candidates progressing into clinical trials since 2000, no candidate to date has proven superior to acute dieting.
CCK-1R agonist development is restrained by risks of toxicity and unwanted side effects: abdominal cramping, nausea, and pancreatitis, risks associated with prolonged receptor activation. Allosteric modulators, by contrast, bind to topologically distinct regions from agonists to influence affinity, activity and/or efficacy. Allosteric modulators can influence receptors without agonism of their own. A positive allosteric modulator (PAM) for CCK-1R could increase the intensity of signalling only during the physiological window of CCK activation, thus modifying appetite with minimal risk of toxicity or side effects.
In this study we aim to investigate the structural mechanisms of allosteric modulation of CCK-1R by a range of different PAMs with different cooperativities with the endogenous agonist CCK. This will be achieved by determining active-state structures of CCK-1R in complex with CCK and allosteric modulators, in complex with transducer proteins by single particle cryo-EM.
To this goal, expression of a CCK-1R with a mimetic small G protein and accessory proteins have been optimised for complex formation, and a range of ligands with a spectrum of agonism and allosteric modulation have been acquired.
Structures of CCK-1R in complex with allosteric modulators will reveal novel allosteric sites for drug discovery.