Structural Insights into Molecular Recognition and Receptor Activation in Chemokine-Chemokine Receptor Complexes

摘要

The chemokine system is a key player in the functioningof theimmune system and a sought-after target for drug candidates. The numberof experimental structures of chemokines in complex with chemokinereceptors has increased rapidly over the past few years, providingessential information for rational development of chemokine receptorligands. Here, we perform a comparative analysis of all chemokine-chemokinereceptor structures, with the aim of characterizing the molecularrecognition processes and highlighting the relationships between chemokinestructures and functional processes. The structures show conservedinteraction patterns between the chemokine core and the receptor N-terminus,while interactions near ECL2 display subfamily-specific features.Detailed analyses of the interactions of the chemokine N-terminaldomain in the 7TM cavities reveal activation mechanisms for CCR5,CCR2, and CXCR2 and a mechanism for biased agonism in CCR1.