PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons
E-Collection

Subtly different

SBKB [doi:10.1038/sbkb.2011.06]
Featured Article - March 2011
Short description: The crystal structure of the D3 dopamine receptor reveals how to selectively target D2-like receptors.

The structure of D3R suggests strategies for designing therapeutics to distinguish between D2-like dopamine receptors.

Dopamine is a crucial neurotransmitter that affects many functions in the brain, acting through the five dopamine receptor subtypes. These G protein–coupled receptors (GPCRs) are further divided into subfamilies on the basis of whether they activate or deactivate adenylyl cyclase (the D1-like or D2-like receptors, respectively). Within the subfamilies, the receptors are very similar, as demonstrated by the high degree of identity between the D2-like receptors D2R and D3R. This similarity has made it difficult to selectively target D2R or D3R, which is desirable for the treatment of schizophrenia or drug abuse.

To address this challenge, Stevens and colleagues (PSI ATCG3D) solved the X-ray crystal structure of D3R in complex with the D2R and D3R inhibitor eticlopride. The structure shows that D3R has a typical GPCR seven-transmembrane domain core with multiple extracellular (ECL) and cytoplasmic (ICL) loops. Two slightly different conformational states of the ICL2 loop were seen, suggesting that this loop may modulate the activity of the receptor. Overall, D3R is structurally very similar to the β2-adrenergic receptor (β2AR), although several shifts can be seen in the positions of the helices that form the core of the receptor. Interestingly, the ionic lock—a stabilizing salt bridge interaction in GPCRs that was thought to play a major factor in stabilizing the receptors in the inactive conformation—can be seen in the D3R structure, the first time this has been shown for a GPCR structure.

Eticlopride bound D3R in a similar location as did the ligand-binding pocket in the β2AR structure, interacting with 18 different residues. Of those residues, 17 are conserved in the D2R interaction with eticlopride, in agreement with the similar affinity of D2R and D3R for eticlopride and underscoring the difficulty in targeting the two receptors individually. Using the structure of D3R, the authors generated a homology model of D2R, which revealed some subtle, but important, differences between the two receptors. Notably, differences can be seen in the extracellular half of helix I and the extracellular electrostatic surfaces, both of which could affect ligand binding. Molecular docking of R-22, a D3R-selective agonist, showed that, in addition to using the same binding pocket as eticlopride, R-22 also utilizes a second binding pocket that involves residues not conserved between the two receptors. Molecular dynamics simulations of D2R confirmed that this second binding pocket has an altered packing relative to D3R, allowing for discrimination between ligands.

Although the differences between D2R and D3R may seem minor, biochemists will no doubt be able to exploit them. The structure of D3R will be foundational to the efforts to develop inhibitors that can distinguish between these two D2-like receptors.

Steve Mason

References

  1. E.Y.T. Chien et al. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.
    Science 330, 1091-1095 (2010). doi:10.1126/science.1197410

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health