Adhesion G protein-coupled receptors as drug targets. Structural basis for regulation of GPR56/ADGRG1 by its alternatively spliced extracellular domains. in G Protein-Coupled Receptors in Health and Disease, Part B Vol. Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing. Adhesion G protein-coupled receptors in nervous system development and disease. Sticky signaling-adhesion class G protein-coupled receptors take the stage. The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. Dihydromunduletone is a small-molecule selective adhesion G protein-coupled receptor antagonist. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Mechanisms of adhesion G protein–coupled receptor activation. Vizurraga, A., Adhikari, R., Yeung, J., Yu, M. Collectively, these results enable us to propose a general model for aGPCR activation. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGR元)). Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood 2, 3, 4, 5. Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface 1. Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell–cell and cell–extracellular matrix interactions 1.
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