8vti

Latrophilin-3 (ADGRL3) HormR and GAIN domains in the context of the holoreceptor

spinqualitylabelsall models 8vti, resolution 3.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8vti is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.9Å Ligands: BMA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AGRL3_HUMAN Plays a role in cell-cell adhesion and neuron guidance via its interactions with FLRT2 and FLRT3 that are expressed at the surface of adjacent cells (PubMed:26235030). Plays a role in the development of glutamatergic synapses in the cortex. Important in determining the connectivity rates between the principal neurons in the cortex.[UniProtKB:Q80TS3] Publication Abstract from PubMed Adhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECRs) containing a conserved GAIN domain that precedes their seven-pass transmembrane domain (7TM). Ligand binding and mechanical force applied on the ECR regulate receptor function. However, how the ECR communicates with the 7TM remains elusive, because the relative orientation and dynamics of the ECR and 7TM within a holoreceptor is unclear. Here, we describe the cryo-EM reconstruction of an aGPCR, Latrophilin3/ADGRL3, and reveal that the GAIN domain adopts a parallel orientation to the transmembrane region and has constrained movement. Single-molecule FRET experiments unveil three slow-exchanging FRET states of the ECR relative to the transmembrane region within the holoreceptor. GAIN-targeted antibodies, and cancer-associated mutations at the GAIN-7TM interface, alter FRET states, cryo-EM conformations, and receptor signaling. Altogether, this data demonstrates conformational and functional coupling between the ECR and 7TM, suggesting an ECR-mediated mechanism for aGPCR activation. Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function.,Kordon SP, Cechova K, Bandekar SJ, Leon K, Dutka P, Siffer G, Kossiakoff AA, Vafabakhsh R, Arac D Nat Commun. 2024 Dec 4;15(1):10545. doi: 10.1038/s41467-024-54836-4. PMID:39627215 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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