Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy

Area of Science:

• Structural Biology
• Neuroendocrinology
• Pharmacology

Background:

• Vasoactive intestinal polypeptide receptor (VIP1R), a class B G protein-coupled receptor, is implicated in neuronal, metabolic, and inflammatory diseases.
• Limited structural information hinders understanding of VIP1R's mechanism and drug discovery potential.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy structure of human VIP1R bound to PACAP27 and a Gs heterotrimer.
• To elucidate the molecular basis of PACAP27 binding and VIP1R activation.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to visualize the receptor-ligand-G protein complex.
• A NanoBiT tethering strategy was utilized to stabilize the complex for structural determination.

Main Results:

• The cryo-EM structure of human VIP1R complexed with PACAP27 and Gs heterotrimer was successfully resolved.
• PACAP27 binds to VIP1R via its N-terminus within the transmembrane bundle, inducing a receptor-specific G protein coupling mechanism.

Conclusions:

• The determined structure provides critical insights into the molecular mechanisms of PACAP27 binding and VIP1R activation.
• The NanoBiT tethering methodology offers a valuable approach for studying other challenging protein complexes.