Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.

This gene encodes a G protein-coupled receptor family member. It belongs to the chemokine receptor family of GPCRs. Within this family, ACKR3 is classified as a class A GPCR. This GPCR protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP) and was considered to be an orphan receptor. It is now classified as a chemokine receptor able to bind the chemokines CXCL12/SDF-1 and CXCL11. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. Alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. Whereas some reports claim that the receptor induces signaling following ligand binding, recent findings in zebrafish suggest that CXCR7 functions primarily by sequestering the chemokine CXCL12.

Another study has provided evidence that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins, and thus has functions beyond ligand sequestration.

ACKR3 has also been shown to sequester endogenous opioid peptides and is thought to modulate their activity.

In 2013, the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology subcommittee for chemokine receptors reevaluated C-X-C chemokine receptor type 7 (CXCR7) and classified it as an atypical chemokine receptor, leading to its renaming as atypical chemokine receptor 3 (ACKR3). Additional names that have been mentioned in the literature, albeit less frequently, include GPR159 and Orphan receptor RDC1, the latter being a term primarily found in older literature.

ACKR3 stands out as an atypical receptor due to its β-arrestin-biased signaling nature. In the case of a β-arrestin-biased receptor like ACKR3, when it is treated with an unbiased ligand, it triggers signaling pathways solely mediated by β-arrestin. What sets ACKR3 apart is its absence of G-protein involvement, which distinguishes it from typical GPCRs.

Despite being considered atypical, the functions of ACKR3 do not imply that it acts as a completely inactive receptor for CXCL12. On the contrary, extensive literature supports the notion of ACKR3 engaging in active signaling, which is believed to rely on arrestin-mediated mechanisms. Nevertheless, its role as a decoy receptor for CXCL12/SDF1 is well-established. This is evident by the significantly higher affinity of CXCL12 binding to ACKR3/CXCR7 compared to CXCR4, along with its constant internalization facilitated by the recruitment of β-arrestin, without known downstream signaling events.

In addition to CXCL12, ACKR3 engages with multiple ligands, encompassing CXCL11, macrophage inhibitory factor (MIF), adrenomedullin (ADM), opioid peptides such as nociceptin, dynorphin, and enkephalin, as well as the viral chemokine vCCL2/viral macrophage inflammatory protein-II.