title: Structural basis of ligand interaction with atypical chemokine receptor 3.
abstract: Chemokines 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.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0684, La Jolla, California, 92093, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Gustavsson
authors.affiliation: Center for Proteomics and Bioinformatics and Department of Nutrition, Case Western Reserve University School of Medicine, 10009 Euclid Avenue, Cleveland, Ohio 44109, USA.
authors.forename: Liwen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0684, La Jolla, California, 92093, USA.
authors.forename: Noortje
authors.initials: N
authors.lastname: van Gils
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0684, La Jolla, California, 92093, USA.
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Stephens
authors.affiliation: ChemoCentryx Inc., 850 W Maude Avenue, Mountain View, California 94043, USA.
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.affiliation: ChemoCentryx Inc., 850 W Maude Avenue, Mountain View, California 94043, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.affiliation: Center for Proteomics and Bioinformatics and Department of Nutrition, Case Western Reserve University School of Medicine, 10009 Euclid Avenue, Cleveland, Ohio 44109, USA.
authors.forename: Sichun
authors.identifier: 0000-0002-1726-0576
authors.initials: S
authors.lastname: Yang
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0684, La Jolla, California, 92093, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: Center for Proteomics and Bioinformatics and Department of Nutrition, Case Western Reserve University School of Medicine, 10009 Euclid Avenue, Cleveland, Ohio 44109, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0684, La Jolla, California, 92093, USA.
authors.forename: Irina
authors.identifier: 0000-0001-9083-7039
authors.initials: I
authors.lastname: Kufareva
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0684, La Jolla, California, 92093, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
mesh_terms: D054377:Chemokine CXCL12 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D054387:Receptors, CXCR / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C501896:ACKR3 protein, human; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D008024:Ligands; D054387:Receptors, CXCR