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Sci Signal. 2017 May 23;10(480). pii: eaai8529. doi: 10.1126/scisignal.aai8529.

Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2.

Author information

1
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
2
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
3
Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre; and Centre for Medical Research, University of Western Australia, Crawley and Dimerix Bioscience Limited, Nedlands, Western Australia, Australia.
4
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. martin.stone@monash.edu meri.canals@monash.edu.
5
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. martin.stone@monash.edu meri.canals@monash.edu.

Abstract

Chemokines and their receptors collectively orchestrate the trafficking of leukocytes in normal immune function and inflammatory diseases. Different chemokines can induce distinct responses at the same receptor. In comparison to monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), the chemokines MCP-2 (CCL8) and MCP-3 (CCL7) are partial agonists of their shared receptor CCR2, a key regulator of the trafficking of monocytes and macrophages that contribute to the pathology of atherosclerosis, obesity, and type 2 diabetes. Through experiments with chimeras of MCP-1 and MCP-3, we identified the chemokine amino-terminal region as being the primary determinant of both the binding and signaling selectivity of these two chemokines at CCR2. Analysis of CCR2 mutants showed that the chemokine amino terminus interacts with the major subpocket in the transmembrane helical bundle of CCR2, which is distinct from the interactions of some other chemokines with the minor subpockets of their receptors. These results suggest the major subpocket as a target for the development of small-molecule inhibitors of CCR2.

PMID:
28536301
DOI:
10.1126/scisignal.aai8529
[Indexed for MEDLINE]

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