Structure-function guided modeling of chemokine-GPCR specificity for the chemokine XCL1 and its receptor XCR1
- 3 September 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 12 (597)
- https://doi.org/10.1126/scisignal.aat4128
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 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.Keywords
Funding Information
- National Institutes of Health (AI058072)
- National Institutes of Health (HL134253)
- National Institutes of Health (GM080202)
- National Institutes of Health (GM080202)
- National Institutes of Health (CA236182)
- Ministry of Education, Culture, Sports, Science, and Technology (S1411037)
- Lundbeckfonden
- Novo Nordisk
- Carlsberg Foundation
- Hørslev Foundation
This publication has 87 references indexed in Scilit:
- Allosteric and Orthosteric Sites in CC Chemokine Receptor (CCR5), a Chimeric Receptor ApproachOnline Journal of Public Health Informatics, 2011
- Alternate States of Proteins Revealed by Detailed Energy Landscape MappingJournal of Molecular Biology, 2011
- Chemokines and chemokine receptors: new insights into cancer-related inflammationTrends in Molecular Medicine, 2010
- The Cytomegalovirus UL146 Gene Product vCXCL1 Targets Both CXCR1 and CXCR2 as an AgonistOnline Journal of Public Health Informatics, 2010
- Multiple Switches in G Protein-Coupled Receptor ActivationTrends in Pharmacological Sciences, 2009
- Interconversion between two unrelated protein folds in the lymphotactin native stateProceedings of the National Academy of Sciences of the United States of America, 2008
- An Engineered Second Disulfide Bond Restricts Lymphotactin/XCL1 to a Chemokine-like Conformation with XCR1 Agonist ActivityBiochemistry, 2007
- Structural Basis of Chemokine Receptor Function—A Model for Binding Affinity and Ligand SelectivityBioscience Reports, 2006
- Cytokines in cancer pathogenesis and cancer therapyNature Reviews Cancer, 2004
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996