G protein-coupled receptors (GPCRs) are membrane proteins and are an important drug target class responsible for over one-third of current therapeutics on the market. Adenosine receptors are broadly distributed in the human body and perform many vital functions. All four adenosine receptor subtypes (A1AR, A2aAR, A2BAR, and A3AR) are activated by endogenous small molecule adenosine. Therapeutically adenosine receptors have been pursued for the treatments of disorders associated with cardiovascular function, pain, inflammation and immunity, Parkinson’s disease, and many others. However, therapeutic targeting of adenosine receptors is challenging due to their broad distribution, the high similarity between different adenosine receptor subtypes, and their ability to initiate multiple signaling cascades simultaneously.
In my talk, I will show how x-ray crystallography and cryo-electron microscopy allowed us to gain insights into the molecular organization of multiple adenosine receptor subtypes, understand their activation mechanism, expose previously unappreciated allosteric pockets, and explain the unusual properties of the biased agonists. Insights from this structural work, coupled with biochemistry, pharmacology, and animal studies, can facilitate the future development of novel small molecules targeting these receptors.