Structural basis of ligand interaction with atypical chemokine receptor 3
Copyright policy )Structural basis of ligand interaction with atypical chemokine receptor 3
AbstractChemokines drive cell migration through their interactions with seven-transmembrane (7TM) chemokine receptors on cell surfaces. The atypical chemokine receptor 3 (ACKR3) binds chemokines CXCL11 and CXCL12 and signals exclusively through β-arrestin-mediated pathways, without activating canonical G-protein signalling. This receptor is upregulated in numerous cancers making it a potential drug target. Here we collected over 100 distinct structural probes from radiolytic footprinting, disulfide trapping, and mutagenesis to map the structures of ACKR3:CXCL12 and ACKR3:small-molecule complexes, including dynamic regions that proved unresolvable by X-ray crystallography in homologous receptors. The data are integrated with molecular modelling to produce complete and cohesive experimentally driven models that confirm and expand on the existing knowledge of the architecture of receptor:chemokine and receptor:small-molecule complexes. Additionally, we detected and characterized ligand-induced conformational changes in the transmembrane and intracellular regions of ACKR3 that elucidate fundamental structural elements of agonism in this atypical receptor.
- University of California, San Diego United States
- Amsterdam UMC Netherlands
- University of California, San Francisco United States
- Case Western Reserve University United States
- University of Montana United States
Models, Molecular, 570, 1.1 Normal biological development and functioning, Science, 610, Ligands, Article, Models, Receptors, 2.1 Biological and endogenous factors, Humans, CXCR, Cancer, Receptors, CXCR, Q, Molecular, Biological Sciences, Chemokine CXCL12, HEK293 Cells, Chemical Sciences, Biochemistry and Cell Biology, Generic health relevance, Protein Binding, Signal Transduction
Models, Molecular, 570, 1.1 Normal biological development and functioning, Science, 610, Ligands, Article, Models, Receptors, 2.1 Biological and endogenous factors, Humans, CXCR, Cancer, Receptors, CXCR, Q, Molecular, Biological Sciences, Chemokine CXCL12, HEK293 Cells, Chemical Sciences, Biochemistry and Cell Biology, Generic health relevance, Protein Binding, Signal Transduction
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