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TitleStructural basis of CXC chemokine receptor 2 activation and signalling.
Journal, issue, pagesNature, Vol. 585, Issue 7823, Page 135-140, Year 2020
Publish dateJul 1, 2020
AuthorsKaiwen Liu / Lijie Wu / Shuguang Yuan / Meng Wu / Yueming Xu / Qianqian Sun / Shu Li / Suwen Zhao / Tian Hua / Zhi-Jie Liu /
PubMed AbstractChemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer. Although ample effort has ...Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions such as inflammation and cancer. Although ample effort has been invested into the structural investigation of the chemokine receptors and receptor-chemokine recognition, 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 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 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.
External linksNature / PubMed:32610344
MethodsEM (single particle) / X-ray diffraction
Resolution3.2 - 3.5 Å
Structure data

EMDB-0877, PDB-6lfm:
Cryo-EM structure of a class A GPCR
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-0879, PDB-6lfo:
Cryo-EM structure of a class A GPCR monomer
Method: EM (single particle) / Resolution: 3.4 Å

PDB-6lfl:
Crystal structure of a class A GPCR
Method: X-RAY DIFFRACTION / Resolution: 3.2 Å

Chemicals

ChemComp-EBX:
4-[[3,4-bis(oxidanylidene)-2-[[(1~{R})-1-(4-propan-2-ylfuran-2-yl)propyl]amino]cyclobuten-1-yl]amino]-~{N},~{N}-dimethyl-3-oxidanyl-pyridine-2-carboxamide

ChemComp-CLR:
CHOLESTEROL / Cholesterol

Source
  • homo sapiens (human)
  • pyrococcus abyssi (strain ge5 / orsay) (archaea)
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / G protein coupled-receptor

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