Insights into the Activation Mechanism of HCA1, HCA2, and HCA3

Hydroxy-carboxylic acid receptors HCA1, HCA2, and HCA3
can be activated
by important intermediates of energy metabolism. Despite the research
focusing on HCA2, its clinical application has been limited by adverse
effects. Therefore, the role of HCA1 as a promising target for the
treatment of lipolysis warrants further exploration. As HCAs exhibit
high similarity when activated with diverse selective agonists, a
conserved yet unique activation mechanism for HCAs remains undisclosed.
Herein, we unveil the cryo-electron microscopy structures of the 3,5-DHBA-HCA1-Gi
signaling complex, the acifran- and MK6892-bound HCA2-Gi signaling
complexes, and the acifran-HCA3-Gi signaling complex. Comparative
analysis across HCAs reveals key residues in HCA1 contributing to
the stabilization of the ligand-binding pocket. Furthermore, chimeric
complexes and mutational analyses identify residues that are pivotal
for HCA2 and HCA3 selectivity. Our findings elucidate critical structural
insights into the mechanisms of ligand recognition and activation
within HCA1 and broaden our comprehension of ligand specificity binding
across the HCA family.