Structural perspectives on chemokine receptors.
Kanwal Kayastha1, Yangli Zhou1, Steffen Brünle1
1Leiden Institute of Chemistry, Faculty of Science, Leiden University, Einsteinweg 55, Leiden 2333 CC, The Netherlands.
Biochemical Society Transactions
|June 10, 2024
Summary
Chemokine receptors, key immune targets, are structurally understood for drug discovery. New insights reveal allosteric modulation and biased signaling mechanisms, advancing therapeutic strategies.
Area of Science:
- Immunology
- Structural Biology
- Pharmacology
Background:
- Chemokine receptors are crucial for immune responses and significant drug targets.
- Recent advancements in structural elucidation have deepened our understanding of these receptors.
- Allosteric modulation and biased signaling are emerging concepts in chemokine receptor research.
Purpose of the Study:
- To provide a timeline of structural achievements in chemokine receptor research.
- To discuss intracellular negative allosteric modulation and orthosteric receptor activation mechanisms.
- To explore the concept of biased signaling and G-protein binding differences.
Main Methods:
- Review of structural elucidation studies.
- Analysis of allosteric modulation mechanisms.
- Investigation of orthosteric activation and biased signaling pathways.
Main Results:
- Intracellular allosteric modulators target a conserved motif in transmembrane helices 7 and 8.
- Chemokine recognition involves multiple sites (CRS1, CRS2, CRS1.5, CRS3), with CRS3 determining ligand specificity.
- Specific residues (e.g., extracellular loop 2 residue 45.51, Y2917.43) and C-terminal phosphorylation influence signaling bias.
Conclusions:
- Structural insights into chemokine receptors facilitate drug discovery efforts.
- Understanding allosteric modulation and biased signaling is key to developing targeted therapeutics.
- Detailed knowledge of chemokine-receptor interactions and signaling pathways opens new avenues for immune system modulation.
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