Student Posters 51st Lorne Proteins Conference 2026

Allosteric modulators at the D2R (#310)

Caitlin Owyong 1 , Jesse Mobbs 1 , David Thal 1
  1. Monash Institute of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

The Dopamine Receptor 2 (D2R) has emerged as a promising target for the treatment of disorders such as Schizophrenia, Parkinson’s Disease and Attention Deficit/Hyperactivity Disorder (ADHD). While medications for each disorder are in clinical use, their various limitations mean fundamental treatment needs remain unmet. Drugs in current use for D2R disorders target the receptor’s orthosteric binding site. This site is highly conserved across all five dopamine receptors. Ligands designed to bind the orthosteric site are hence not specific to the D2R, and off-target binding can cause dangerous side-effects.

Allosteric sites are binding pockets outside of the orthosteric site, which are more unique to receptor subtypes. Targeting allosteric sites specific to the D2R would circumvent non-specific activation of other dopamine receptors, thus reducing the risk of side effects. Molecules that bind allosteric sites can have an activating or inactivating effect. These are known as Positive or Negative Allosteric Modulators (PAMs or NAMs).

Activation of the D2R causes inhibition of dopamine binding. PAM binding has potential to decrease dopamine signalling, which is helpful in diseases of dopamine excess like Schizophrenia. Conversely, NAM binding could increase dopamine signalling, with potential to counter the dopamine deficiencies of Parkinson’s Disease and ADHD. Our research group has identified a PAM (UCB-PAM 2) and a NAM (SB269652) with therapeutic potential at the D2R.

Currently there are no structures of the D2R in complex with an allosteric modulator. My PhD project aims to purify the D2R in complex with both UCB-PAM 2 and SB269652 and visualise the respective active and inactive structures with cryo-EM.

My efforts to date have included testing different D2R constructs with fusion proteins and stabilising nanobody fragments, with successful negative stain data of the D2R in complex with an orthosteric agonist. This poster details my methods of virus passaging and protein purification.

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