9p8a | pdb_00009p8a
NTSR1-G11-NTS(8-13) GTP-Bound Complex in the Canonical, AHD Closed State 3DVA Separated 2 (C-Closed*-GTP)
Structural highlights
DiseaseGNA11_HUMAN Phakomatosis cesioflammea;Uveal melanoma;Phakomatosis cesiomarmorata;Autosomal dominant hypocalcemia;Familial hypocalciuric hypercalcemia type 2;Cutis marmorata telangiectatica congenita. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionGNA11_HUMAN Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades (PubMed:31073061). The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state (PubMed:31073061). Signaling by an activated GPCR promotes GDP release and GTP binding (PubMed:31073061). The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal (PubMed:31073061). Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:31073061). Signaling is mediated via phospholipase C-beta-dependent inositol lipid hydrolysis for signal propagation: activates phospholipase C-beta: following GPCR activation, GNA11 activates PLC-beta (PLCB1, PLCB2, PLCB3 or PLCB4), leading to production of diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (PubMed:31073061). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs) (PubMed:27852822). Together with GNAQ, required for heart development (By similarity).[UniProtKB:P21278][1] [2] Publication Abstract from PubMedG-protein-coupled receptors (GPCRs) are capable of signalling through four families of G protein alpha subunits. Although hundreds of nucleotide-free GPCR-G protein complex structures have been solved, the mechanism of G protein subtype selectivity remains poorly understood, with recent studies suggesting a role for dynamic nucleotide-bound intermediate states(1,2). Here we use time-resolved cryo-electron microscopy to visualize the GTP-induced activation of Galpha(i1)betagamma and Galpha(11)betagamma heterotrimers bound to the neurotensin receptor 1 (NTSR1), which has been demonstrated to be highly promiscuous in G protein coupling and to possess unusual conformations in the nucleotide-free complex. We resolve ensembles of states along the G protein activation pathway, with differences in the structures and their relative populations between Galpha(i1) and Galpha(11). Structural analysis reveals a key role for several motifs, including intracellular loop 2 (ICL2) and ICL3, in stabilizing the observed intermediate states. Our results are supported by molecular dynamics simulations and kinetic bioluminescence resonance energy transfer experiments, which reveal that the stability of these intermediate states and the signalling of various G proteins are correlated with ICL2 and ICL3 sequences. Single-molecule fluorescence assays of GTP-induced NTSR1-G protein complex dissociation reveal that NTSR1 is liberated significantly faster from Galpha(11), consistent with the relative lack of stable Galpha(11)-GTP intermediate states compared with Galpha(i1). These findings highlight that transient intermediate-state complexes along the G protein activation pathway have an important role in G protein selection that cannot be explained by nucleotide-free states alone. Snapshots of the dynamic basis of NTSR1 G protein subtype promiscuity.,Vo AA, Modak A, Lu S, Blanchard SC, Lambert NA, Robertson MJ Nature. 2026 Mar 11. doi: 10.1038/s41586-026-10120-7. PMID:41813894[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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