Grand opening of structure-guided design for novel opioids

Twelve years after the publication of the first crystal structure of a G-protein-coupled receptor (GPCR), experimental crystal structures of the four opioid receptor subtypes have made their entrance into the literature in the most extraordinary way, that is, all at once. Not only do these crystal structures contribute unprecedented molecular details of opioid ligand binding and specificity, but they also represent important tools for structure-based approaches to guide the discovery of safer and more efficient opioid therapeutics. We provide here an overview of these latest breakthroughs in the structural biology of GPCRs with a focus on differences and similarities between the four opioid receptor structures, as well as their limitations, in the context of challenges for translation of this new knowledge from bench to bedside.