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Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1. Sci Signal 2019 Sep 03;12(597)

Date

09/05/2019

Pubmed ID

31481523

Pubmed Central ID

PMC6733756

DOI

10.1126/scisignal.aat4128

Scopus ID

2-s2.0-85071750983   1 Citation

Abstract

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 (Val, Gly, Ser, and Glu) contribute a large fraction of the binding energy to its receptor XCR1, whereas residues near the disulfide bond-forming residue Cys 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 Glu of XCL1 and Tyr and Arg of XCR1. Subsequent mutation of Tyr and Arg 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.

Author List

Fox JC, Thomas MA, Dishman AF, Larsen O, Nakayama T, Yoshie O, Rosenkilde MM, Volkman BF

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




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