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TitleStructural basis of CXC chemokine receptor 1 ligand binding and activation.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 4107, Year 2023
Publish dateJul 11, 2023
AuthorsNaito Ishimoto / Jae-Hyun Park / Kouki Kawakami / Michiko Tajiri / Kenji Mizutani / Satoko Akashi / Jeremy R H Tame / Asuka Inoue / Sam-Yong Park /
PubMed AbstractNeutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and ...Neutrophil granulocytes play key roles in innate immunity and shaping adaptive immune responses. They are attracted by chemokines to sites of infection and tissue damage, where they kill and phagocytose bacteria. The chemokine CXCL8 (also known as interleukin-8, abbreviated IL-8) and its G-protein-coupled receptors CXCR1 and CXCR2 are crucial elements in this process, and also the development of many cancers. These GPCRs have therefore been the target of many drug development campaigns and structural studies. Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. Unlike the closely related CXCR2, CXCR1 strongly prefers to bind CXCL8 in its monomeric form. The model shows that steric clashes would form between dimeric CXCL8 and extracellular loop 2 (ECL2) of CXCR1. Consistently, transplanting ECL2 of CXCR2 onto CXCR1 abolishes the selectivity for the monomeric chemokine. Our model and functional analysis of various CXCR1 mutants will assist efforts in structure-based drug design targeting specific CXC chemokine receptor subtypes.
External linksNat Commun / PubMed:37433790 / PubMed Central
MethodsEM (single particle)
Resolution3.41 Å
Structure data

35351

8ic0

EMDB-35351, PDB-8ic0:
Cryo-EM structure of CXCL8 bound C-X-C chemokine receptor 1 in complex with Gi heterotrimer
Method: EM (single particle) / Resolution: 3.41 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / Chemokine / Interleukin / CXCR / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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