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 () and Cheng Zhang ()
Additional contact information
Youwen Zhuang: The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Heng Liu: University of Pittsburgh
X. Edward Zhou: Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute
Ravi Kumar Verma: Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)
Parker W. de Waal: Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute
Wonjo Jang: Medical College of Georgia, Augusta University
Ting-Hai Xu: Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute
Lei Wang: University of Pittsburgh
Xing Meng: David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Research Institute
Gongpu Zhao: David Van Andel Advanced Cryo-Electron Microscopy Suite, Van Andel Research Institute
Yanyong Kang: Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute
Karsten Melcher: Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute
Hao Fan: Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)
Nevin A. Lambert: Medical College of Georgia, Augusta University
H. Eric Xu: The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Cheng Zhang: University of Pittsburgh

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14728-9

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