| Structural highlights
Function
GNAI1_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 PubMed
G 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
- ↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
- ↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
- ↑ Casiraghi M, Wang H, Brennan PC, Habrian C, Hübner 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. Structure and dynamics determine G protein coupling specificity at a class A GPCR. Sci Adv. 2025 Mar 21;11(12):eadq3971. PMID:40106559 doi:10.1126/sciadv.adq3971
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