A new analysis has elucidated the structure and activation mechanisms of the human receptor HCAR1, which is involved in many metabolic and inflammatory conditions. By teasing apart the mechanisms of the receptor’s activation, the findings could inform research into therapies that target HCAR1. This receptor is found in fat, neurons, skeletal muscle, and other tissue types, and fills various roles in metabolism and in reducing inflammation. The receptor’s wide-ranging functions suggest that it could be a solid target in cancer and stroke, as well as in neurodegenerative conditions such as Alzheimer’s disease. However, there are still no potent activators or inhibitors of HCAR1, and scientists know little about how the receptor recognizes its binding partners and becomes activated. Here, Mengru Gao and colleagues harnessed cryo-electron microscopy to interrogate the structure and function of HCAR1 in complex with the G protein subunit Gαi1. They studied HCAR1 in its unbound state and when it was bound to either lactate – its normal metabolite ligand – or a synthetic activator named CHBA. The authors found that HCAR1 had a smaller and more compact ligand-binding pocket compared with those of other HCARs, such as HCAR2. Lactate bound fairly weakly to HCAR1 and only activated the receptor at relatively high concentrations, but CHBA was more potent and bound more stably. Further research revealed that HCAR1 became self-activated through structural rearrangement of its extracellular loop 2 region. “This study fills gaps in our knowledge of the structure of HCAR1 and elucidates the differences between self-activation and ligand-dependent activation of the receptor, potentially providing a structural and theoretical basis for the design of inverse, selective, and high-efficiency agonists,” the authors conclude.
