Structural basis of ligand interaction with atypical chemokine receptor 3

Martin Gustavsson, Liwen Wang, Noortje van Gils, Bryan S Stephens, Penglie Zhang, Thomas J Schall, Sichun Yang, Ruben Abagyan, Mark R Chance, Irina Kufareva, Tracy M Handel

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)14135
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 18 Jan 2017

Cite this

Gustavsson, M., Wang, L., van Gils, N., Stephens, B. S., Zhang, P., Schall, T. J., ... Handel, T. M. (2017). Structural basis of ligand interaction with atypical chemokine receptor 3. Nature Communications, 8, 14135. https://doi.org/10.1038/ncomms14135