Allosteric modulation of the chemokine receptor-chemokine CXCR4-CXCL12 complex by tyrosine sulfation.

The chemokine receptor CXCR4 and its cognate ligand CXCL12 mediate pathways that lead to cell migration and chemotaxis. Although the structural details of related receptor-ligand complexes have been resolved, the roles of the N-terminal domain of the receptor and post-translational sulfation that are determinants of ligand selectivity and affinity remain unclear. Here, we analyze the structural dynamics induced by receptor sulfation by combining molecular dynamics, docking and network analysis. The sulfotyrosine residues, 7Ys, 12Ys and 21Ys allow the N-terminal domain of the apo-sulfated receptor to adopt an "open" conformation that appears to facilitate ligand binding. The overall topology of the CXCR4-CXCL12 complex is independent of the sulfation state, but an extensive network of protein-protein interactions characterizes the sulfated receptor, in line with its increased ligand affinity. The altered interactions of sulfotyrosine residues, such as 21Ys-47R replacing the 21Y-13F interaction, propagate via allosteric pathways towards the receptor lumen. In particular, our results suggest that the experimentally-reported receptor-ligand interactions 262D-8R and 277E-12R could be dependent on the sulfation state of the receptor and need to be carefully analyzed. Our work is an important step in understanding chemokine-receptor interactions and how post-translational modifications could modulate receptor-ligand complexes.