Journal
FEBS JOURNAL
Volume 289, Issue 2, Pages 386-393Publisher
WILEY
DOI: 10.1111/febs.15865
Keywords
activation; chemokine receptor; cryo-EM; CXCL8; CXCR2
Categories
Funding
- CAS Strategic Priority Research Program [XDB37030104]
- National Science Fund for Distinguished Young Scholars [32022038]
- National Key Research and Development Program of China [2018YFA0507000]
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The study reveals the binding modes between CXCL8 and CXCR2, CXCR2 and G protein, as well as the detailed binding pattern of the allosteric antagonist 00767013. Further analysis also uncovers the unique shallow-pocket activation mechanism of CXCR2 and suggests a potential role of cholesterol in allosteric modulation in chemokine receptors.
The C-X-C motif chemokine CXCL8 (interleukin-8, IL-8) and its receptor chemokine receptor 2 (CXCR2) mediate neutrophil migration during cell development and inflammatory responses and thus are related to numerous inflammatory diseases and cancers. We have determined the cryo-electron microscopy structure of CXCL8 bound CXCR2 coupled to G(i) protein, as well as the crystal structure of inactive CXCR2 in complex with a designed allosteric antagonist. These results reveal the binding modes between CXCL8 and CXCR2, CXCR2 and G protein, and the detailed binding pattern of the allosteric antagonist, 00767013. Further structural analysis of the inactive- and active- states of CXCR2 reveals the unique shallow-pocket activation mechanism of C-X-C chemokine receptors and promotes our understanding on how a G protein-coupled receptor (GPCR) is activated by an endogenous protein molecule. In addition, the cholesterol molecule is observed in the activated CXCR2 structure, providing the structural basis of the potential allosteric modulation role of cholesterol in chemokine receptors.
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