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

Exploration of diverse agonism of the Calitonin receptor by using high-resolution single particle cryo electron microscopy. (#204)

Rachel Johnson 1 , Matthew Belousoff 1 , Jian-Jun Cao 1 , Patrick Sexton 1 , Denise Wootten 1
  1. Drug Development Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia

Amylin receptors (AMYRs) are heterodimers of the calcitonin (CT) receptor (CTR) and one of three receptor activity-modifying proteins (RAMPs), AMY1R, AMY2R, and AMY3R. Agonism of AMYs and CTRs is a very active area of research as has exciting prospects in the treatment of obesity. Ligands that have the ability to agonise both the CTR and AMYs are considered dual action agonists and have been termed DACRAs (Dual AMYR/CTR agonists). We will present a series of DACRA ligand bound structures of the whole family of AMYs and CTR with all the structures achieving resolutions below 3 angtrom using both 200 kV and 300 kV electron microscopes and present not only the static consensus models, but the difference in 3D conformational variablity in order to describe how a single ligand is able to agonise a diverse range of GPCRs.

  1. 1 Cao, J. et al. A structural basis for amylin receptor phenotype. Science 375, eabm9609, doi:10.1126/science.abm9609 (2022).