Structural basis of stepwise proton sensing-mediated GPCR activation.

ABSTRACT: The regulation of pH homeostasis is crucial in many biological processes vital for survival, growth, and function of life. The pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 and GPR68, play a pivotal role in detecting changes in extracellular proton concentrations, impacting both physiological and pathological states. However, comprehensive understanding of the proton sensing mechanism is still elusive. Here, we determined the cryo-electron microscopy structures of GPR4 and GPR65 in various activation states across different pH levels, coupled with G_s, G_q or G₁₃ proteins, as well as a small molecule NE52-QQ57-bound inactive GPR4 structure. These structures reveal the dynamic nature of the extracellular loop 2 and its signature conform

SUBMITTER: Yue X 

PROVIDER: S-EPMC12134361 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature