Poster Presentation The 48th Lorne Conference on Protein Structure and Function 2023

Structure of the pituitary adenylate cyclase-activating polypeptide 1 receptor bound to its secondary signal transducer Gq (#143)

Theodore Nettleton 1 2 , Sarah J Piper 1 2 , Matthew J Belousoff 1 2 , Patrick M Sexton 1 2 , Denise Wootten 1 2
  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
  2. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia

G protein-coupled receptors (GPCRs) are ubiquitous in humans and are major drug targets. The pituitary adenylate cyclase-activating polypeptide 1 receptor (PAC1R) is a class B1 GPCR implicated in diseases with major burdens on society, including chronic stress disorders such as anxiety and migraine. PAC1R can instigate cell signaling events through G proteins; it does so primarily through the Gs subtype, though also through the secondary signal transducer Gq (1). As both these signaling pathways are involved in PAC1R-mediated disease structural information about PAC1R interactions with these transducers is useful for drug discovery targeting this receptor. Currently, our structural understanding of the PAC1R is limited to active-state Gs bound complexes. Here a structure of the PAC1R in complex with the secondary Gq transducer has been determined. This works expands our structural understanding of PAC1R activation and how class B1 GPCRs can interact with their secondary signal transducers. Ultimately, these insights into PAC1R signalling can aid drug development efforts targeting this receptor.

 

  1. Lu J, Piper SJ, Zhao P, Miller LJ, Wootten D, & Sexton PM (2022). Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors. Int J Mol Sci 23:8069.