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

Zil E. Huma, Julie Sanchez, Herman D. Lim, Jessica L. Bridgford, Cheng Huang, Bradyn J. Parker, Jiann G. Pazhamalil, Benjamin T. Porebski, Kevin D G Pfleger, J. Robert Lane, Meritxell Canals, Martin J. Stone

Research output: Contribution to journalArticleResearchpeer-review

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 fromthe 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. 

Original languageEnglish
Article numbereaai8529
Number of pages13
JournalScience Signaling
Volume10
Issue number480
DOIs
Publication statusPublished - 23 May 2017

Cite this

Huma, Zil E. ; Sanchez, Julie ; Lim, Herman D. ; Bridgford, Jessica L. ; Huang, Cheng ; Parker, Bradyn J. ; Pazhamalil, Jiann G. ; Porebski, Benjamin T. ; Pfleger, Kevin D G ; Lane, J. Robert ; Canals, Meritxell ; Stone, Martin J. / Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. In: Science Signaling. 2017 ; Vol. 10, No. 480.
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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 fromthe 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. ",
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Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. / Huma, Zil E.; Sanchez, Julie; Lim, Herman D.; Bridgford, Jessica L.; Huang, Cheng; Parker, Bradyn J.; Pazhamalil, Jiann G.; Porebski, Benjamin T.; Pfleger, Kevin D G; Lane, J. Robert; Canals, Meritxell; Stone, Martin J.

In: Science Signaling, Vol. 10, No. 480, eaai8529, 23.05.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Huang, Cheng

AU - Parker, Bradyn J.

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AU - Porebski, Benjamin T.

AU - Pfleger, Kevin D G

AU - Lane, J. Robert

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AU - Stone, Martin J.

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