What Do Structures Tell Us About Chemokine Receptor Function and Antagonism?

Abstract

Chemokines and their cell surface G protein-coupled receptors are critical for cell migration not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provide unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs. In parallel, chemokine receptor structures with small molecules reveal complicated and diverse structural foundations of small molecule antagonism and allostery, highlight inherent physicochemical challenges of receptor:chemokine interfaces, and suggest novel epitopes that can be exploited to overcome these challenges. The structures and models promote unique understanding of chemokine receptor biology, including the interpretation of two decades of experimental studies, and will undoubtedly assist future drug discovery endeavors.

Structure of monomeric Interleukin-8 and its interactions with the N-terminal Binding Site-I of CXCR1 by solution NMR spectroscopy

“…Finally, electrostatic interactions attract the ELR motif in IL-8 to the extracellular loops of CXCR1, which constitute Binding Site-II, triggering a conformational change that activates the receptor. A very similar series of events is expected to take place in other chemokine receptors (Kufareva et al 2017). …”

“…Despite extensive studies (Kufareva et al 2017) much remains to be learned about the molecular basis of chemokine-receptor interactions. Here we present the structure of monomeric IL-8(1–66) obtained by deleting the C-terminal residues 67–72, which contribute to the dimerization interface.…”

A unique signal sequence of the chemokine receptor CCR7 promotes package into COPII vesicles for efficient receptor trafficking

“…The initial interaction between a chemokine and its cognate receptor occurs in 2 major steps that seem to be consistent among all chemokine receptors, whereas several additional intermediate interactions have been described for specific chemokines. Overall, the N‐terminus of the receptor is essential for the first step of chemokine binding . Consistent with this paradigm, an N‐terminal peptide of CCR7 was found to bind to the N‐loop and the third β‐strand of CCL21, whereas binding to CCL19 was not addressed in that study.…”

“…Structurally, chemokine receptors span the plasma membrane by 7 transmembrane α‐helices that are connected by 3 extracellular and 3 intracellular loops. The extracellular N‐terminus of the receptor is linked through a disulfide bond to the third extracellular loop and considered to control chemokine binding and ligand specificity . Negatively charged amino acids of the receptor's N‐terminus are generally thought to interact first with the basic core domain of the chemokine ligand, which positions the chemokine's N‐terminus such that it facilitates its insertion into the binding pocked defined by the 7 transmembrane bundles of the receptor .…”

“…The extracellular N‐terminus of the receptor is linked through a disulfide bond to the third extracellular loop and considered to control chemokine binding and ligand specificity . Negatively charged amino acids of the receptor's N‐terminus are generally thought to interact first with the basic core domain of the chemokine ligand, which positions the chemokine's N‐terminus such that it facilitates its insertion into the binding pocked defined by the 7 transmembrane bundles of the receptor . Chemokine receptors are highly dynamic structures and signaling efficiency principally relies on the discrete interaction with the chemokine ligand …”