Chemokines and their receptors: insights from molecular modeling and crystallography

- Chemokine interactions with receptors trigger cell migration in immunity and cancer.
- 2015 brought high-resolution insights into the structural basis of these interactions.
- Complex architecture is conserved but features diverse, functionally distinct epitopes.
- Chemokine dimerization interfaces are repurposed for receptor binding.
- Novel epitopes hold promise for fine-tuned pharmacological modulation.

Chemokines are small secreted proteins that direct cell migration in development, immunity, inflammation, and cancer. They do so by binding and activating specific G protein coupled receptors on the surface of migrating cells. Despite the importance of receptor:chemokine interactions, their structural basis remained unclear for a long time. In 2015, the first atomic resolution insights were obtained with the publication of X-ray structures for two distantly related receptors bound to chemokines. In conjunction with experiment-guided molecular modeling, the structures suggest a conserved receptor:chemokine complex architecture, while highlighting the diverse details and functional roles of individual interaction epitopes. Novel findings promote the development and detailed structural interpretation of the canonical two-site hypothesis of receptor:chemokine recognition, and suggest new avenues for pharmacological modulation of chemokine receptors.

160