Structural basis of CXC chemokine receptor 2 activation and signalling

Nature. 2020 Sep;585(7823):135-140. doi: 10.1038/s41586-020-2492-5. Epub 2020 Jul 1.


Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer1. Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor-chemokine recognition2-4, 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 Gi 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 Gi 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Chemokines / classification
  • Chemokines / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Humans
  • Interleukin-8 / metabolism
  • Models, Molecular*
  • Protein Binding
  • Receptors, Interleukin-8B / chemistry*
  • Receptors, Interleukin-8B / metabolism*
  • Signal Transduction*
  • Structure-Activity Relationship
  • Substrate Specificity


  • CXCL8 protein, human
  • CXCR2 protein, human
  • Chemokines
  • Interleukin-8
  • Receptors, Interleukin-8B
  • GTP-Binding Protein alpha Subunits, Gi-Go