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

Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1. Sci Signal. 2019 Sep 03;12(597): Authors: Fox JC, Thomas MA, Dishman AF, Larsen O, Nakayama T, Yoshie O, Rosenkilde MM, Volkman BF 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 (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 chan...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research