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.

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