Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias

Yu-Chen Yen, Christopher T Schafer, Martin Gustavsson, Stefanie A Eberle, Pawel K Dominik, Dawid Deneka, Penglie Zhang, Thomas J Schall, Anthony A Kossiakoff, John J G Tesmer, Tracy M Handel

Sci Adv. 2022 Jul 15;8(28):eabn8063.

PMID: 35857509 PMCID: PMC9278869 DOI: 10.1126/sciadv.abn8063

Both CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are activated by the chemokine CXCL12 yet evoke distinct cellular responses. CXCR4 is a canonical G protein-coupled receptor (GPCR), whereas ACKR3 is intrinsically biased for arrestin. The molecular basis for this difference is not understood. Here, we describe cryo-EM structures of ACKR3 in complex with CXCL12, a more potent CXCL12 variant, and a small-molecule agonist. The bound chemokines adopt an unexpected pose relative to those established for CXCR4 and observed in other receptor-chemokine complexes. Along with functional studies, these structures provide insight into the ligand-binding promiscuity of ACKR3, why it fails to couple to G proteins, and its bias toward β-arrestin. The results lay the groundwork for understanding the physiological interplay of ACKR3 with other GPCRs.