Structural basis of CXC chemokine receptor 2 activation and signalling

Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer 1 . Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor–chemokine recognition 2 – 4 , less is known about endogenous chemokine-induced receptor activation and G-protein coupling. Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with G i protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. Our results reveal a unique shallow mode of binding between CXCL8 and CXCR2, and also show the interactions between CXCR2 and G i protein. Further structural analysis of the inactive and active states of CXCR2 reveals a distinct activation process and the competitive small-molecule antagonism of chemokine receptors. In addition, our results provide insights into how a G-protein-coupled receptor is activated by an endogenous protein molecule, which will assist in the rational development of therapeutics that target the chemokine system for better pharmacological profiles. Structures of the G i -coupled CXC chemokine receptor 2 (CXCR2) in complex with CXCL8 and in complex with an allosteric antagonist provide insight into the ligand binding and activation of CXCR2 and its mode of G-protein coupling.