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Structure-activity relationships of chemokines
I Clark-Lewis1, K S Kim, K Rajarathnam
1Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
Journal of Leukocyte Biology
|May 1, 1995
Summary
Chemokines, crucial for immune response, function as monomers. Their receptor binding sites are primarily in the flexible N-terminal region, with conserved structural elements providing a scaffold for function.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- Chemokines (CXC and CC classes) share a conserved alpha/beta structural fold.
- Despite observed aggregation, chemokines function as monomers.
- Understanding chemokine structure-function relationships is key to immune modulation.
Purpose of the Study:
- To elucidate the structural basis of chemokine receptor binding and function.
- To identify conserved and class-specific structural requirements for chemokine activity.
- To explore the potential for developing chemokine antagonists.
Main Methods:
- Structural analysis of chemokine classes (CXC and CC).
- Investigation of protein conformation in solution.
- Mapping of receptor binding sites and functional regions.
Main Results:
- The NH2-terminal 20 residues are critical for receptor binding and are conformationally flexible.
- A conserved structural scaffold, including disulfide bonds, dictates the conformation of binding sites.
- For CC chemokines, distinct regions within the N-terminus mediate receptor binding and activation.
- High-affinity CC chemokine analogs that act as antagonists were identified.
Conclusions:
- Chemokine function relies on a conserved structural scaffold and flexible N-terminal binding regions.
- The distinct binding and activation sites in CC chemokines enable the development of specific antagonists.
- Structural insights pave the way for targeted immunomodulatory therapies.