leadXpro has just elucidated the world’s first structure of a proton-sensing GPCR target
Proton-sensing G protein–coupled receptors (H–GPCRs) form a subfamily of proteins (GPR65, GPR4 and GPR68) that detect variation of acidity in the extracellular milieu and trigger intracellular signaling in response to alterations in extracellular pH. These receptors have been linked to several important pH-dependent physiological activities including respiration, renal adaption, secretion and responsiveness to insulin, mechanosensation and cellular chemotaxis. GPR4 and GPR68 are highly expressed in endothelial cells and vascular smooth muscle cells, respectively, while expression of GPR65 appears to be more restricted to the immune system. These receptors are implicated in multiple pathological processes, such as asthma, inflammatory bowel disease and tumor cell invasiveness, making them interesting targets for therapy.
To date, no structural information has been reported for the entire H+ activated GPCR family. Thus, the leadXpro high-resolution structures of GPR65, by Cryo-EM, represents a major advancement in our ability to understand these targets and use structure-based methods to design new therapeutics.