Molecular Cell
Volume 77, Issue 3, 6 February 2020, Pages 656-668.e5
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Article
Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation

https://doi.org/10.1016/j.molcel.2020.01.012Get rights and content
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Highlights

  • Cryo-EM structure reveals how CRF1R interacts with CRF and the Gs signaling protein

  • Cryo-EM structure reveals interactions of Pac1nR with PACAP-38 and Gs

  • Evolutionary related GPCRs have greater conservation in peptide and G protein binding

Summary

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.

Keywords

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

Cited by (0)

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These authors contributed equally

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Present address: Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4002 Basel, Switzerland

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