Skip to main content

Research Repository

Advanced Search

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.

Authors

Zil E. Huma

JULIE SANCHEZ JULIE.SANCHEZ@NOTTINGHAM.AC.UK
Research Fellow - Pharmacology Cell Biologist

Herman D. Lim

Jessica L. Bridgford

Cheng Huang

Bradyn J. Parker

Jiann G. Pazhamalil

Benjamin T. Porebski

Kevin D. G. Pfleger

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

Martin J. Stone



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. 2017 © The Authors.

Citation

Huma, Z. E., Sanchez, J., Lim, H. D., Bridgford, J. L., Huang, C., Parker, B. J., …Stone, M. J. (2017). Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2. Science Signaling, 10(480), Article eaai8529. https://doi.org/10.1126/scisignal.aai8529

Journal Article Type Article
Acceptance Date May 5, 2017
Online Publication Date May 23, 2017
Publication Date May 23, 2017
Deposit Date Mar 6, 2019
Publicly Available Date Mar 6, 2019
Journal Science Signaling
Print ISSN 1945-0877
Electronic ISSN 1937-9145
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 10
Issue 480
Article Number eaai8529
DOI https://doi.org/10.1126/scisignal.aai8529
Keywords chemokine receptor CCR2; monocyte chemotactic protein; protein inhibitor; CCL2 protein, human; CCL7 protein, human; CCR2 protein, human; chemokine; chemokine receptor CCR2; monocyte chemotactic protein 1; monocyte chemotactic protein 3; protein binding; a
Public URL https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019598451&doi=10.1126%2fscisignal.aai8529&partnerID=40&md5=a5caa3e173d4e8915900acf29ae1a939
Publisher URL http://stke.sciencemag.org/content/10/480/eaai8529
Additional Information This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling, Vol. 10, Issue 480, on 23 May 2017, DOI: 10.1126/scisignal.aai8529 .

Files





You might also like



Downloadable Citations