Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling

Youwen Zhuang, Heng Liu, X. Edward Zhou, Ravi Kumar Verma, Parker W. de Waal, Wonjo Jang, Ting Hai Xu, Lei Wang, Xing Meng, Gongpu Zhao, Yanyong Kang, Karsten Melcher, Hao Fan, Nevin A. Lambert, H. Eric Xu, Cheng Zhang

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Abstract

Formylpeptide receptors (FPRs) as G protein-coupled receptors (GPCRs) can recognize formylpeptides derived from pathogens or host cells to function in host defense and cell clearance. In addition, FPRs, especially FPR2, can also recognize other ligands with a large chemical diversity generated at different stages of inflammation to either promote or resolve inflammation in order to maintain a balanced inflammatory response. The mechanism underlying promiscuous ligand recognition and activation of FPRs is not clear. Here we report a cryo-EM structure of FPR2-Gi signaling complex with a peptide agonist. The structure reveals a widely open extracellular region with an amphiphilic environment for ligand binding. Together with computational docking and simulation, the structure suggests a molecular basis for the recognition of formylpeptides and a potential mechanism of receptor activation, and reveals conserved and divergent features in Gi coupling. Our results provide a basis for understanding the molecular mechanism of the functional promiscuity of FPRs.

Original languageEnglish (US)
Article number885
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zhuang, Y., Liu, H., Edward Zhou, X., Kumar Verma, R., de Waal, P. W., Jang, W., Xu, T. H., Wang, L., Meng, X., Zhao, G., Kang, Y., Melcher, K., Fan, H., Lambert, N. A., Eric Xu, H., & Zhang, C. (2020). Structure of formylpeptide receptor 2-Gi complex reveals insights into ligand recognition and signaling. Nature communications, 11(1), [885]. https://doi.org/10.1038/s41467-020-14728-9