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Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1

Key amino acids in the chemokine XCL1 mediate its specificity for and activation of its receptor XCR1. Modeling ligand-receptor specificity Ligand-receptor interactions trigger many cellular behaviors and changes that underlie various physiologic processes. Understanding what determines the specificity of these interactions, therefore, can explain disease and inform the development of targeted therapeutics. Using a hybrid modeling approach, Fox et al. generated a model for the chemokine XCL1 in complex with its G protein–coupled receptor XCR1 and identified key interaction sites. Changes within a region of XCL1 that determined its binding energy to XCR1 changed the activity of the receptor and, consequently, cell migration. In addition to showing the power of such hybrid approaches, these findings specifically on this chemokine signaling axis may have implications for diseases associated with altered dendritic and T cell immune responses. Chemokines interact with their G protein–coupled receptors (GPCRs) through a two-step, two-site mechanism and, through this interaction, mediate various homeostatic and immune response mechanisms. Upon initial recognition of the chemokine by the receptor, the amino terminus of the chemokine inserts into the orthosteric pocket of the GPCR, causing conformational changes that trigger intracellular signaling. There is considerable structural and functional evidence to suggest that the amino acid composition and length of the chemokine amino terminus is critical for GPCR activation, complementing the size and amino acid composition of the orthosteric pocket. However, very few structures of a native chemokine-receptor complex have been solved. Here, we used a hybrid approach that combines structure-function data with Rosetta modeling to describe key contacts within a chemokine-GPCR interface. We found that the extreme amino-terminal residues of the chemokine XCL1 (Val1, Gly2, Ser3, and Glu4) contribute a large fraction of the binding energy to its receptor XCR1, whereas residues near the disulfide bond–forming residue Cys11 modulate XCR1 activation. Alterations in the XCL1 amino terminus changed XCR1 activation, as determined by assessing inositol triphosphate accumulation, intracellular calcium release, and directed cell migration. Computational analysis of XCL1-XCR1 interactions revealed functional contacts involving Glu4 of XCL1 and Tyr117 and Arg273 of XCR1. Subsequent mutation of Tyr117 and Arg273 led to diminished binding and activation of XCR1 by XCL1. These findings demonstrate the utility of a hybrid approach, using biological data and homology modeling, to study chemokine-GPCR interactions.