Eligible Student Poster 49th Lorne Conference on Protein Structure and Function 2024

Structural Insights into Positive Allosteric Modulation at the M4 mAChR (#121)

Michaela Kaoullas 1 2 , Jesse Mobbs 1 2 , Celine Valant 1 , David Thal 1 2
  1. Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
  2. Monash Institute of Pharmaceutical Sciences, ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Melbourne, Victoria, Australia

The M4 muscarinic acetylcholine receptor (mAChR) has emerged as an exciting new target for the treatment of CNS disorders, such as schizophrenia. A major challenge is the selective activation of the M4 mAChR due to the mAChRs having highly conserved orthosteric binding sites. We have recently determined cryogenic-electron microscopy (cryo-EM) structures of the M4 mAChR bound to a new generation of selective positive allosteric modulators (PAMs), compound XY6. The PAM XY6 has a 10-fold improved binding affinity versus the previous generation of M4 PAMs such as LY2033298 and VU0467154 (Vuckovic et al., 2023). Understanding why XY6 has improved binding properties in comparison to previous generations of M4 PAMs will facilitate the design of future M4 mAChRs based therapeutics.

This project aims to determine how residues in the allosteric site of the M4 mAChR contribute to the binding affinity (pKB), binding cooperativity (⍺), allosteric agonism (