9jfz | pdb_00009jfz
Cryo-EM structure of intermediate state GPR4 complexed with miniGs/q in pH7.5
Structural highlights
DiseaseGNAS2_HUMAN Pseudopseudohypoparathyroidism;Pseudohypoparathyroidism type 1A;Progressive osseous heteroplasia;Polyostotic fibrous dysplasia;Monostotic fibrous dysplasia;Pseudohypoparathyroidism type 1C;Pseudohypoparathyroidism type 1B;McCune-Albright syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Most affected individuals have defects in methylation of the gene. In some cases microdeletions involving the STX16 appear to cause loss of methylation at exon A/B of GNAS, resulting in PHP1B. Paternal uniparental isodisomy have also been observed. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAS2_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers in numerous signaling pathways controlled by G protein-coupled receptors (GPCRs) (PubMed:17110384). Signaling involves the activation of adenylyl cyclases, resulting in increased levels of the signaling molecule cAMP (PubMed:26206488, PubMed:8702665). GNAS functions downstream of several GPCRs, including beta-adrenergic receptors (PubMed:21488135). Stimulates the Ras signaling pathway via RAPGEF2 (PubMed:12391161).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe 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 G(13) 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 conformations in different receptor states, and disclose the proton sensing mechanism mediated by networks of extracellular histidine and carboxylic acid residues. Notably, we unexpectedly captured partially active intermediate states of both GPR4-G(s) and GPR4-G(q) complexes, and identified a unique allosteric binding site for NE52-QQ57 in GPR4. By integrating prior investigations with our structural analysis and mutagenesis data, we propose a detailed atomic model for stepwise proton sensation and GPCR activation. These insights may pave the way for the development of selective ligands and targeted therapeutic interventions for pH sensing-relevant diseases. Structural basis of stepwise proton sensing-mediated GPCR activation.,Yue X, Peng L, Liu S, Zhang B, Zhang X, Chang H, Pei Y, Li X, Liu J, Shui W, Wu L, Xu H, Liu ZJ, Hua T Cell Res. 2025 Apr 11. doi: 10.1038/s41422-025-01092-w. PMID:40211064[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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