7x10
ADGRL3/miniG12 complexADGRL3/miniG12 complex
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedAdhesion G-protein-coupled receptors (aGPCRs) play key roles in a diversity of physiologies. A hallmark of aGPCR activation is the removal of the inhibitory GAIN domain and the dipping of the cleaved stalk peptide into the ligand-binding pocket of receptors; however, the detailed mechanism remains obscure. Here, we present cryoelectron microscopy (cryo-EM) structures of ADGRL3 in complex with G(q), G(s), G(i), and G(12). The structures reveal unique ligand-engaging mode, distinctive activation conformation, and key mechanisms of aGPCR activation. The structures also reveal the uncharted structural information of GPCR/G(12) coupling. A comparison of G(q), G(s), G(i), and G(12) engagements with ADGRL3 reveals the key determinant of G-protein coupling on the far end of alphaH5 of Galpha. A detailed analysis of the engagements allows us to design mutations that specifically enhance one pathway over others. Taken together, our study lays the groundwork for understanding aGPCR activation and G-protein-coupling selectivity. Structural insights into adhesion GPCR ADGRL3 activation and G(q), G(s), G(i), and G(12) coupling.,Qian Y, Ma Z, Liu C, Li X, Zhu X, Wang N, Xu Z, Xia R, Liang J, Duan Y, Yin H, Xiong Y, Zhang A, Guo C, Chen Z, Huang Z, He Y Mol Cell. 2022 Nov 17;82(22):4340-4352.e6. doi: 10.1016/j.molcel.2022.10.009. , Epub 2022 Oct 28. PMID:36309016[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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