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From Proteopedia
Structure of the LM189-Bound beta2AR-Gi Complex
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedG protein-coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The beta(2)-adrenergic receptor is an example of GPCR with high selectivity for Galphas, the stimulatory G protein for adenylyl cyclase, and much weaker for the Galphai family of G proteins inhibiting adenylyl cyclase. By developing a Galphai-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Galphas and Galphai. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways. Structure and dynamics determine G protein coupling specificity at a class A GPCR.,Casiraghi M, Wang H, Brennan PC, Habrian C, Hubner H, Schmidt MF, Maul L, Pani B, Bahriz SMFM, Xu B, Staffen N, Assafa TE, Chen B, White E, Sunahara RK, Inoue A, Xiang YK, Lefkowitz RJ, Isacoff EY, Nucci N, Gmeiner P, Lerch MT, Kobilka BK Sci Adv. 2025 Mar 21;11(12):eadq3971. doi: 10.1126/sciadv.adq3971. Epub 2025 Mar , 19. PMID:40106559[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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