Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20.

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Abstrakt

Tytuł:: Structural basis for chemokine receptor CCR6 activation by the endogenous protein ligand CCL20.
Autorzy:: Wasilko DJ; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Johnson ZL; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Ammirati M; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Che Y; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Griffor MC; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Han S; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Wu H; Discovery Sciences, Medicine Design, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA. .
Źródło:: Nature communications [Nat Commun] 2020 Jun 15; Vol. 11 (1), pp. 3031. Date of Electronic Publication: 2020 Jun 15.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Chemokine CCL20/*metabolism
Receptors, CCR6/*chemistry
Receptors, CCR6/*metabolism
Chemokine CCL20/chemistry ; Chemokine CCL20/genetics ; Cryoelectron Microscopy ; Humans ; Ligands ; Protein Binding ; Receptors, CCR6/genetics ; Receptors, G-Protein-Coupled ; Signal Transduction
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Substance Nomenclature:: 0 (CCL20 protein, human)
0 (CCR6 protein, human)
0 (Chemokine CCL20)
0 (Ligands)
0 (Receptors, CCR6)
0 (Receptors, G-Protein-Coupled)
Entry Date(s):: Date Created: 20200617 Date Completed: 20200826 Latest Revision: 20210615
Update Code:: 20240105
PubMed Central ID:: PMC7295996
DOI:: 10.1038/s41467-020-16820-6
PMID:: 32541785
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Chemokines are important protein-signaling molecules that regulate various immune responses by activating chemokine receptors which belong to the G protein-coupled receptor (GPCR) superfamily. Despite the substantial progression of our structural understanding of GPCR activation by small molecule and peptide agonists, the molecular mechanism of GPCR activation by protein agonists remains unclear. Here, we present a 3.3-Å cryo-electron microscopy structure of the human chemokine receptor CCR6 bound to its endogenous ligand CCL20 and an engineered Go. CCL20 binds in a shallow extracellular pocket, making limited contact with the core 7-transmembrane (TM) bundle. The structure suggests that this mode of binding induces allosterically a rearrangement of a noncanonical toggle switch and the opening of the intracellular crevice for G protein coupling. Our results demonstrate that GPCR activation by a protein agonist does not always require substantial interactions between ligand and the 7TM core region.

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