What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?
Irina Kufareva1, Martin Gustavsson1, Yi Zheng1
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093; email: ikufareva@ucsd.edu , thandel@ucsd.edu.
Annual Review of Biophysics
|May 24, 2017
Summary
New structural insights into chemokine receptors and their interactions with chemokines and small molecules are advancing our understanding of cell migration in health and disease. These findings are crucial for developing novel therapeutics targeting inflammatory diseases and cancer.
Area of Science:
- Molecular biology
- Structural biology
- Immunology
Background:
- Chemokines and G protein-coupled receptors (GPCRs) are vital for cell migration.
- Dysregulation of these pathways contributes to inflammatory diseases and cancer.
Purpose of the Study:
- To elucidate the atomic details of chemokine recognition and receptor activation.
- To understand the structural basis of small molecule antagonism and allostery in chemokine receptors.
- To identify novel therapeutic targets for chemokine receptor-mediated diseases.
Main Methods:
- X-ray crystallography of chemokine-receptor complexes.
- Computational modeling and simulations.
- Biophysical and biochemical assays.
Main Results:
- Detailed atomic structures of two chemokine-receptor complexes revealed key interaction interfaces.
- Small molecule-bound chemokine receptor structures elucidated mechanisms of antagonism and allostery.
- Computational models expanded understanding to multiple receptor:chemokine pairs.
Conclusions:
- Structural and computational insights provide a deeper understanding of chemokine receptor biology.
- These findings offer a foundation for future drug discovery efforts targeting chemokine pathways.
- Novel epitopes for therapeutic intervention have been identified.
Keywords:
G protein–coupled receptorallosterycrystallographydruggabilitymolecular modelingreceptor activationMore Related Videos
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