PMID- 28536301
OWN - NLM
STAT- MEDLINE
DCOM- 20180104
LR  - 20180104
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 10
IP  - 480
DP  - 2017 May 23
TI  - Key determinants of selective binding and activation by the monocyte 
      chemoattractant proteins at the chemokine receptor CCR2.
LID - eaai8529 [pii]
LID - 10.1126/scisignal.aai8529 [doi]
AB  - 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.
CI  - Copyright (c) 2017, American Association for the Advancement of Science.
FAU - Huma, Zil E
AU  - Huma ZE
AUID- ORCID: 0000-0002-4257-1675
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
FAU - Sanchez, Julie
AU  - Sanchez J
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
FAU - Lim, Herman D
AU  - Lim HD
AD  - Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash 
      University, Parkville, Victoria 3052, Australia.
FAU - Bridgford, Jessica L
AU  - Bridgford JL
AUID- ORCID: 0000-0001-8381-1121
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
AD  - Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash 
      University, Parkville, Victoria 3052, Australia.
FAU - Huang, Cheng
AU  - Huang C
AUID- ORCID: 0000-0002-4575-1233
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
FAU - Parker, Bradyn J
AU  - Parker BJ
AUID- ORCID: 0000-0001-5727-4879
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
FAU - Pazhamalil, Jiann G
AU  - Pazhamalil JG
AUID- ORCID: 0000-0002-9865-316X
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
FAU - Porebski, Benjamin T
AU  - Porebski BT
AD  - Infection and Immunity Program, Monash Biomedicine Discovery Institute, and 
      Department of Biochemistry and Molecular Biology, Monash University, Clayton, 
      Victoria 3800, Australia.
FAU - Pfleger, Kevin D G
AU  - Pfleger KDG
AD  - 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.
FAU - Lane, J Robert
AU  - Lane JR
AUID- ORCID: 0000-0002-7361-7875
AD  - Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash 
      University, Parkville, Victoria 3052, Australia.
FAU - Canals, Meritxell
AU  - Canals M
AUID- ORCID: 0000-0002-7942-5006
AD  - Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash 
      University, Parkville, Victoria 3052, Australia. martin.stone@monash.edu 
      meri.canals@monash.edu.
FAU - Stone, Martin J
AU  - Stone MJ
AUID- ORCID: 0000-0002-6468-4427
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20170523
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (CCL2 protein, human)
RN  - 0 (CCL7 protein, human)
RN  - 0 (CCR2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CCL7)
RN  - 0 (Chemokines)
RN  - 0 (Receptors, CCR2)
SB  - IM
MH  - Amino Acid Sequence
MH  - Chemokine CCL2/chemistry/metabolism
MH  - Chemokine CCL7/chemistry/metabolism
MH  - Chemokines/*chemistry/*metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Protein Binding
MH  - Receptors, CCR2/*chemistry/genetics/*metabolism
MH  - Sequence Homology
EDAT- 2017/05/26 06:00
MHDA- 2018/01/05 06:00
CRDT- 2017/05/25 06:00
PHST- 2017/05/25 06:00 [entrez]
PHST- 2017/05/26 06:00 [pubmed]
PHST- 2018/01/05 06:00 [medline]
AID - 10/480/eaai8529 [pii]
AID - 10.1126/scisignal.aai8529 [doi]
PST - epublish
SO  - Sci Signal. 2017 May 23;10(480):eaai8529. doi: 10.1126/scisignal.aai8529.