Chemokines simultaneously bind SARS-CoV-2 nucleocapsid protein RNA-binding and dimerization domains.

Viruses express chemokine (CHK)-binding proteins to interfere with the host CHK network and thereby modulate leukocyte migration. SARS-CoV-2 Nucleocapsid (N) protein binds a subset of human CHKs with high affinity, inhibiting their chemoattractant properties. Here, we report that both N's RNA-binding and dimerization domains participate individually in CHK binding. CHKs typically possess independent sites for binding glycosaminoglycans (GAG) and their receptor proteins. We show that the interaction with the N protein occurs through the CHK GAG-binding site, pointing the way to developing compounds that block this interaction for potential anti-coronavirus therapeutics.