Structural perspective of class B1 GPCR signaling.

Class B1 G protein-coupled receptors (GPCRs) play important roles in human physiology and disease pathology. Using cryo-electron microscopy (cryo-EM) and X-ray crystallography, the 3D structures of all 15 members of this receptor subfamily have been determined in recent years at the near-atomic level. Although they share many structural commonalities, they show distinct features in terms of ligand recognition and receptor activation. In-depth structural analyses have yielded valuable insights into the N termini of both peptide hormones and cognate receptors, the outward movement of transmembrane helix 6 (TM6), the allosteric modulation sites located in the transmembrane domain (TMD), and the constitutive signaling bias mediated by receptor splice variants. These provide new directions for the design of better therapeutic agents, thereby making these targets more druggable. The N termini of some peptides that regulate signal transduction, for example, GLP-1 and GLP-2, show different orientations when interacting with their respective receptors, and TIP39 adopts a unique loop conformation at its N-terminus upon binding to PTH2R. The extracellular domain (ECD) of some class B1 receptors is directly involved in signaling. For example, the N-terminus of GLP‐1R folds down towards the TMD to cover the ligand-binding pocket when bound by non-peptidic agonists. The ECD N-terminal α-helix of VIP2R inserts to the cleft between PACAP27 and ECL1 to stabilize peptide binding. The outward movement of TM6 upon receptor activation could be significantly affected by small molecules acting as allosteric modulators, including an ago-allosteric modulator (ago-PAM) and several negative allosteric modulators (NAMs). There are two forms of signaling bias – ligand-dependent and constitutive – that are mediated by splice variants of the wild-type receptor, for example, SV1 of GHRHR. [ABSTRACT FROM AUTHOR]