Dopamine receptor divergence revealed using a common ligand

Abstract

Rational drug design for G protein-coupled receptors (GPCRs) remains a challenging area. A new study from the Xu, Roth, and Zhang groups provides a complete set of active structures for the entire dopamine receptor family bound with rotigotine that will aid in designing selective agonists for these important therapeutic targets.

Figure 1.

D2-like receptors have more divergent binding pockets than D1-like receptors. (A) An overview of the rotigotine bound DAR-G protein complexes, using the D2R-Gi protein structure as an example. The ligand binding pocket is indicated by a magenta box. In the zoom-in views of the ligand binding pocket, (B) and (C), the structures of D1-like and D2-like receptors are overlaid, respectively. The binding site residues are determined based on sidechain atoms within 4.7Å proximity to rotigotine bound in any of the five structures. Conserved residues shared among DARs are depicted in dark grey, while residues conserved within either the D1-like or D2-like subgroup are depicted in light grey. Divergent residues within D2-like subgroup are highlighted in cyan, with the residue identities labeled as D2R/D3R/D4R. The bound rotigotine molecule is in sphere representation.