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Papers In Press, published online ahead of print May 7, 2004
J. Biol. Chem, 10.1074/jbc.M313883200
Submitted on December 18, 2003
Revised on May 7, 2004
Accepted on May 7, 2004

Ligand selectivity and affinity of chemokine receptor CXCR1: Role of N-terminal domain

Lavanya Rajagopalan and Krishna Rajarathnam

Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, TX 77555-1055

Corresponding Author: krrajara{at}utmb.edu

‘ELR’CXC chemokines interleukin-8 (IL-8) and melanoma growth stimulatory activity (MGSA) recruit neutrophils by binding and activating two receptors, CXCR1 and CXCR2. CXCR1 is specific, binding only IL-8 with nanomolar affinity, while CXCR2 is promiscuous, binding all ‘ELR’CXC chemokines with high affinity. Receptor signaling consists of two events: interactions between the ligand N-terminal loop (N-loop) and receptor N-terminal 'ELR' residues (site I), and between the ligand N-terminal and the receptor juxtamembrane domain residues (site II). It is not known how these interactions mediate ligand affinity and selectivity, and whether binding at one site influences binding and function at the other. Sequence analysis and structure-function studies suggest that the receptor N-domain plays an important role in ligand selectivity. Here, we report ligand-binding properties and structural characteristics of the CXCR1 N-domain in solution and in detergent micelles that mimic the native membrane environment. We find that IL-8 binds the N-domain with significantly higher affinity in micelles than in solution (~1 mu M vs. ~20 mu M), and that MGSA does not bind the N-domain in solution, but does in micelles with appreciable affinity (~3 mu M). We find that the N-domain is structured in micelles, and that the entire N-domain interacts with the micelle in an extended fashion. We conclude that the micellar environment constrains the N-domain, and this conformational restraint influences its ligand-binding properties. Most importantly, our data suggest that for both ligands, site I interaction provides similar affinity, and that differential coupling between site I and II interactions are responsible for the observed differences in affinity.


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