ABSTRACT
Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
Subject(s)
Cryoelectron Microscopy/methods , GTP-Binding Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Dynamic Light Scattering , Humans , Microscopy, Electron , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolismABSTRACT
A mild amination protocol of N-heteroaryl alkyl ethers with various amines is described. This transformation is achieved by utilizing simple and readily available base as promoter via C-O bond cleavage, offering a new amination strategy to access several anticancer-active compounds. This work is highlighted by the excellent functional group compatibility, scalability, wide substrate scope, and easy derivatization of a variety of drugs.