Table 6.
Cryo-EM structures of active, peptide-bound, Gs protein-coupled, PAC1R, VPAC1R, and VPAC2R as of June 2022. The PAC1R isoforms solved include PAC1R-null (PAC1nR) with the full-length ECD and PAC1R-short (PAC1sR) with the truncated N-terminal ECD.
| Receptor | Agonist | G Protein 1 | PDB | Resolution |
|---|---|---|---|---|
| PAC1nR [135] | PACAP38 | DNGαs, Gβ1, Gγ2 | 6P9Y | 3.0 Å |
| PAC1nR [139] | PACAP38 | Mini-Gαs, Gβ1, Gγ2 | 6LPB | 3.9 Å |
| PAC1sR [138] | PACAP38 | DNGαs, Gβ1, Gγ2 | 6M1I | 3.5 Å |
| PAC1sR [138] | Maxadilan | DNGαs, Gβ1, Gγ2 | 6M1H | 3.6 Å |
| VPAC1R-LgBiT 2 [136] | PACAP27 | DNGαs, Gβ1-HiBiT, Gγ2 | 6VN7 | 3.2 Å |
| VPAC2R-LgBiT 2 [137] | PACAP27 | DNGαs, Gβ1-HiBiT, Gγ2 | 7VQX 3 | 2.7 Å |
1 Gαs modifications to aid complex stability include the use of a dominant negative (DN)Gαs and a mini-Gαs [284,286]. 2 The VPAC receptors utilized NanoBiT tethering technology to aid complex stability where the receptor is tagged with a large BiT (LgBiT) component and the Gβ1 subunit is tagged with an engineered small BiT (HiBiT) component [136]. 3 In Xu et al., 2022 [137], two PACAP27-bound VPAC2R structures were determined. One with the N-terminal modifications, VPAC2R(24-438) (PDB: 7WBJ), and one with no N-terminal modifications, VPAC2R(1–438) (PDB: 7VQX). As the construct with the N-terminal modifications displayed an altered pharmacology profile, the construct with no N-terminal modifications (PDB: 7VQX) is the construct discussed in this review.