Extended Data Fig. 6: G protein-coupling to FFA2.
From: Allosteric modulation and biased signalling at free fatty acid receptor 2
a, Interactions between FFA2 and the α5 helix of Gi (from the structure of FFA2 with AZ-1729 and Gi) or miniGq (from the structure of FFA2 with compound187 and miniGq). b, Interactions between FFA2 and the αN helix of Gi or miniGq. Polar interactions are shown as black dashed lines. Specifically, in both structures, D350H5.22 (G protein numbering) in Gi, or E242H5.22 in mGαi/s/q forms a polar interaction with R121ICL2 in FFA2. Additionally, L348H5.20 and L353H5.25 in Gi form hydrophobic interactions with V1113.54, F2025.61, M2065.65, and L2236.36 of FFA2, while the corresponding residues, L240H5.20 and L245H5.25 in mGαi/s/q, also form direct interactions with these residues in FFA2. Notably, residues P114ICL2, V115ICL2, and L119ICL2 in ICL2 of FFA2 inserts into a hydrophobic pocket formed by Gi residues L194S3.01, F336H5.08, I343H5.15, and I344H5.16, or mGαi/s/q residues F228H5.08, I235H5.15, and L236H5.16, stabilizing a significant hydrophobic environment. c, Structural comparison of the α5 and αN helices in the TUG-1375-AZ-1729-FFA2-Gi (yellow), TUG-1375-compound187-FFA2-miniGq (yellow green), and TUG-1375-compound-FFA2-Gi (pink) complexes. The α5 helix adopts a highly similar conformation across all three structures, whereas the αN helix exhibits greater variability. d, Polar interactions between FFA2 and the α5 helix of miniGq (right panel), which are missing in the structures with Gi (left panel). Polar interactions are shown as black dashed lines.
