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

Jia Duan, Dan-dan Shen, X. Edward Zhou, Peng Bi, Qiu-feng Liu, Yang-xia Tan, You-wen Zhuang, Hui-bing Zhang, Pei-yu Xu, Si-Jie Huang, Shan-shan Ma, Xin-heng He, Karsten Melcher, Yan Zhang (), H. Eric Xu () and Yi Jiang ()
Additional contact information
Jia Duan: Chinese Academy of Sciences
Dan-dan Shen: Zhejiang University School of Medicine
X. Edward Zhou: Van Andel Institute
Peng Bi: Zhejiang University School of Medicine
Qiu-feng Liu: Chinese Academy of Sciences
Yang-xia Tan: Chinese Academy of Sciences
You-wen Zhuang: Chinese Academy of Sciences
Hui-bing Zhang: Zhejiang University School of Medicine
Pei-yu Xu: Chinese Academy of Sciences
Si-Jie Huang: Chinese Academy of Sciences
Shan-shan Ma: Chinese Academy of Sciences
Xin-heng He: Chinese Academy of Sciences
Karsten Melcher: Van Andel Institute
Yan Zhang: Zhejiang University School of Medicine
H. Eric Xu: Chinese Academy of Sciences
Yi Jiang: Chinese Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17933-8

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