7SF7

LPHN3 (ADGRL3) 7TM domain bound to tethered agonist in complex with G protein heterotrimer

Summary for 7SF7

• Entry DOI: 10.2210/pdb7sf7/pdb
• EMDB information: 25076 25077
• Descriptor: Isoform 1 of Adhesion G protein-coupled receptor L3, G protein subunit 13 (Gi2-mini-G13 chimera), Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (5 entities in total)
• Functional Keywords: adhesion gpcr, lphn3, latrophilin, adgrl3, tethered agonist, stalk, stachel, minig13, g13 heterotrimer, g protein, cryoem, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 106166.21

Authors

Barros-Alvarez, X.,Panova, O.,Skiniotis, G. (deposition date: 2021-10-03, release date: 2022-04-27, Last modification date: 2024-10-09)

Primary citation

Barros-Alvarez, X.,Nwokonko, R.M.,Vizurraga, A.,Matzov, D.,He, F.,Papasergi-Scott, M.M.,Robertson, M.J.,Panova, O.,Yardeni, E.H.,Seven, A.B.,Kwarcinski, F.E.,Su, H.,Peroto, M.C.,Meyerowitz, J.G.,Shalev-Benami, M.,Tall, G.G.,Skiniotis, G.
The tethered peptide activation mechanism of adhesion GPCRs.
Nature, 604:757-762, 2022

PubMed Abstract: 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. 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. 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. 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 ADGRL3)). 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. 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. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.

PubMed: 35418682
DOI: 10.1038/s41586-022-04575-7

Experimental method

ELECTRON MICROSCOPY (2.9 Å)