mProX™ Human GPR21 Stable Cell Line

Thian-Sze Wong et al. "Cryo-EM structure of orphan G protein-coupled receptor GPR21." MedComm, 2023
GPR21, a member of the orphan G protein-coupled receptor (GPCR) class A, is associated with developing type 2 diabetes (T2DM), a multifactorial metabolic disease resulting from pancreatic beta-cell dysfunction, decreased insulin production, insulin resistance, and obesity. While the endogenous ligands for human GPR21 are yet to be identified, animal studies have suggested its potential as a therapeutic target for T2DM treatment. However, the mechanisms underlying GPR21 self-activation remain unknown. In a co-expression analysis, it was observed that GPR21 can form a stable complex with an unreported subtype of Galpha protein, Galphas. To further understand the structural mechanisms of GPR21 activation, cryo-electron microscopy (cryo-EM) and single-particle analysis were employed to reveal the high-resolution structure of GPR21-Galphas complexes. The electron density map of the GPR21-Galphas complex provided evidence that GPR21 can couple to Galphas protein under physiological conditions. This suggests that GPR21 may mediate previously unexplored pathways in both normal and pathological conditions, which requires further investigation. Through structure-guided mutagenesis and biochemical analysis, it was determined that extracellular loop 2 (ECL2) of GPR21 is crucial for the receptor's ability to transduce intracellular signals via cAMP. These new structural insights reveal a novel signaling cascade mediated by human GPR21, with ECL2 playing a crucial role, providing fundamental information for potential structure-based drug development in the future.
Thian-Sze Wong et al. "Cryo-EM structure of orphan G protein-coupled receptor GPR21." MedComm, 2023
Pubmed: 36721851   DOI: 10.1002/mco2.205

Xi Lin et al. "Cryo-EM structures of orphan GPR21 signaling complexes." Nature communications, 13 Jan. 2023
The class-A orphan G protein-coupled receptor (GPCR) known as GPR21 has recently been identified as a potential therapeutic target for type 2 diabetes and other metabolic disorders. Despite the absence of any known endogenous agonist or synthetic ligand, this receptor has shown high basal activity in coupling to multiple G proteins. In this study, researchers present the structures of ligand-free human GPR21 bound to heterotrimeric miniGs and miniG15 proteins. They have also identified an agonist-like motif in extracellular loop 2 (ECL2) and a potential new ligand binding site. Interestingly, the binding of G proteins is facilitated by a flexible portion of transmembrane helix 6 (TM6) with minimal outward movement. These findings provide insight into GPR21's signal transduction and offer the opportunity for future deorphanization and development of modulators for this receptor.
Xi Lin et al. "Cryo-EM structures of orphan GPR21 signaling complexes." Nature communications, 13 Jan. 2023
Pubmed: 36639690   DOI: 10.1038/s41467-023-35882-w