Structural basis of chemokine receptor function--a model for binding affinity and ligand selectivity

Abstract

Chemokine receptors play fundamental roles in human physiology from embryogenesis to inflammatory response. The receptors belong to the G-protein coupled receptor class, and are activated by chemokine ligands with a range of specificities and affinities that result in a complicated network of interactions. The molecular basis for function is largely a black box, and can be directly attributed to the lack of structural information on the receptors. Studies to date indicate that function can be best described by a two-site model, that involves interactions between the receptor N-domain and ligand N-terminal loop residues (site-I), and between receptor extracellular loop and the ligand N-terminal residues (site-II). In this review, we describe how the two-site model could modulate binding affinity and ligand selectivity, and also highlight some of the unique chemokine receptor features, and their role in function.

Fig. 1

A schematic showing how chemokines recruit leukocytes. Each step affords an opportunity for regulation and modulation of chemokine function. Chemokine ligands are shown as green circles, and the receptors are shown in brown as a series of stacked lines (corresponding to the 7 transmembrane helices). Chemokine ligand dimerization is shown but receptor dimerization is not shown for simplicity

Fig. 2

Specificity and Promiscuity of Chemokine-receptor interactions. The receptors are shown inside the circle and the ligands outside the circle. The systematic nomenclature for both chemokine ligand and receptors are used, and the commonly used ligand names are shown in brackets. Some chemokines have multiple common names, and we have opted to use just one for simplicity

Fig. 3

A schematic of chemokine structure. The functionally important N-terminal and N-loop residues are highlighted by arrows, and the strands and the helix are labeled

Fig. 4

A model of chemokine ligand-receptor interaction (reproduced from ref. 74). The ligand N-loop residues interact with the receptor N-terminal domain residues (site I), and the ligand N-terminal residues interact with the receptor exoloops and trans-membrane residues (site II)