Extended Data Fig. 6: Comparisons of peptide hormone binding pockets and small molecule agonist binding sites of class B GPCRs.
From: Conserved class B GPCR activation by a biased intracellular agonist
The PCO371 binding pocket is different from both peptide binding pockets and other small molecule binding pockets of class B GPCRs. (a–d) Comparisons the ligand-binding pockets between PCO371 and peptides of PTH1R. The receptor is shown in surface representation and colored in light sea green and PCO371 in crimson is shown as sticks. In three PTH-, PTHrP- and LA-PTH-bound PTH1R-Gs complex structures, the receptors are shown in surface representation and colored in royal blue, dark khaki and dark orchid, respectively. PTH, PTHrP and LA-PTH are colored in light coral, medium violet red and forest green, respectively. They are shown as sticks and ribbon (PDB: 8HA0, 8HAF and 6NBF). G proteins and Nb35 are omitted for clarity. (e–l) Comparisons of small molecule agonist binding sites of class B GPCRs. Superimposition of the PTH1R (light sea green) in complex with Gs bound to PCO371 (crimson) with the GLP1R in complexes with Gs bound to different non-peptidic ligands, including small molecule agonists: TT-OAD2(PDB: 6ORV; TT-OAD2: dark orchid, GLP1R: burly wood); RGT1383 (PDB: 7C2E; RGT1383: green, GLP1R: light salmon); PF-06882961(PDB: 6X1A; PF-06882961: dark orange, GLP1R: thistle); CHU-128 (PDB: 6X19; CHU-128: yellow, GLP1R: rosy brown); LY3502970 (PDB: 6XOX; LY3502970: sandy brown, GLP1R: silver); Boc5 (PDB: 7X8R; Boc5:blue, GLP1R: dark sea green) and WB4-24 (PDB:7X8S; WB4-24: indigo, GLP1R: light steel blue) and with an allosteric ligand, Compound 2, (PDB: 7EVM; Compound 2: goldenrod, GLP1R: tomato), G proteins and Nb35 are omitted for clarity.
