Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation

Yi Lynn Liang, Matthew J. Belousoff, Peishen Zhao, Cassandra Koole, Madeleine M. Fletcher, Tin T. Truong, Villy Julita, George Christopoulos, H. Eric Xu, Yan Zhang, Maryam Khoshouei, Arthur Christopoulos, Radostin Danev, Patrick M. Sexton, Denise Wootten

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75 Citations (Scopus)


Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.

Original languageEnglish
Pages (from-to)656-668.e5
Number of pages18
JournalMolecular Cell
Issue number3
Publication statusPublished - 6 Feb 2020


  • agonist efficacy
  • class B GPCR
  • corticotropin-releasing factor
  • cryoelectron microscopy
  • G protein-coupled receptor
  • pituitary adenylate cyclase-activating peptide
  • receptor activation

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