Oral Presentation 51st Lorne Proteins Conference 2026

Structures, dynamics and function of PAC1 receptor variants: staying 'in the loop'. (132852)

Jessica Lu 1 2 , Giuseppe Deganutti 3 , Miaomiao Li 1 , Laura Humphrys 1 , Yandi Li 1 , Theo Nettleton 1 , Hariprasad Venugopal 4 , Patrick Sexton 1 2 , Denise Wootten 1 2 , Elva Zhao 1 2 , Sarah J Piper 1 2
  1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
  2. ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
  3. Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry, UK
  4. Ramaciotti Centre for CryoEM, Monash University, Clayton, VIC, Australia

G protein-coupled receptors (GPCRs) have a broad range of regulatory metabolic effects and are therefore important drug targets. The PAC1R, a Class B1 peptide hormone GPCR, is a potential drug target for the treatment of migraine and other central nervous system (CNS) disorders. The receptor can be activated by the endogenous peptide agonists VIP and PACAP which have diverse cellular signalling outcomes; the former having lower affinity and the latter having higher affinity and higher potency to activate the receptor 1. 
More interestingly, the PAC1 receptor exists as multiple splice variants, including PAC1nR ('null' variant) and PAC1sR ('short' variant, missing 21 amino acids), located at a highly flexible loop of the extracellular domain of the receptor. Interestingly, despite the distal location of this splice site, signalling and regulatory functions are globally enhanced at PAC1sR relative to PAC1nR, yet the pharmacology of other PAC1R agonists (including PACAP) is similar between these two splice variants.

Using biochemistry, cryo-EM structures, MD simulations and mutagenesis, we propose mechanisms for this altered signalling by the VIP agonist, mediated through distinct interactions of receptor loop regions as well as distinct receptor-agonist interactions in these variants 2.

Furthermore, we load our structural data into Blender, an open-source 3D computer graphics software, to develop 3D animations based on our experimental data, and tell visual stories about how these receptor variants work 3.

  1. Piper, S.J., Deganutti, G., Lu, J. et al. Understanding VPAC receptor family peptide binding and selectivity. Nat Commun 13, 7013 (2022). https://doi.org/10.1038/s41467-022-34629-3
  2. unpublished
  3. 3D animations of GPCRs on YouTube: http://www.youtube.com/@piperproteinproductions