Cryo-EM structure of the bicarbonate receptor GPR30

G-protein-coupled receptor 30 (GPR30) is a bicarbonate receptor that plays a vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with bicarbonate ions remain elusive. There is no consensus on a drug that targets GPR30, and the difficulty in the pharmacological analysis has limited biological and drug discovery researches on GPR30. Here, we present the cryo-electron microscopy structure of human GPR30 in the presence of bicarbonate ions at 3.2 Å resolution. Our structure reveals unique extracellular pockets and critical residues for bicarbonate binding and activation. Functional assays demonstrate that mutations in these residues impair bicarbonate-induced GPR30 activation, underscoring their importance in receptor function. This study also provides insights into the G-protein coupling, highlighting the structural divergence between GPR30 and other GPCRs. Our findings not only advance the understanding of the role of GPR30 in pH homeostasis but also pave the way for the development of high-affinity drugs targeting GPR30 for therapeutic interventions in diseases associated with acid-base imbalance.