8G2Y

Cryo-EM structure of ADGRF1 coupled to miniGs/q

Summary for 8G2Y

• Entry DOI: 10.2210/pdb8g2y/pdb
• EMDB information: 29684
• Descriptor: MiniG alpha s/q chimera, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, agonist, g protein, signaling, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 161147.44

Authors

Jones, D.,Rawson, S.,Blacklow, S. (deposition date: 2023-02-06, release date: 2023-05-10, Last modification date: 2024-10-16)

Primary citation

Jones, D.T.D.,Dates, A.N.,Rawson, S.D.,Burruss, M.M.,Lipper, C.H.,Blacklow, S.C.
Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling.
Nat Commun, 14:2490-2490, 2023

PubMed Abstract: Adhesion G Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to effect cell signalling. We report here that ADGRF1 can signal through all major G protein classes and identify the structural basis for a previously reported Gα preference by cryo-EM. Our structure shows that Gα preference in ADGRF1 may derive from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helix VII and helix VIII at the site of Gα recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Gα signalling is more sensitive to mutation of TA or binding site residues than Gα. Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation.

PubMed: 37120430
DOI: 10.1038/s41467-023-38083-7

Experimental method

ELECTRON MICROSCOPY (3.44 Å)