Atypical chemokine receptor 3 (ACKR3)

Atypical chemokine receptor 3 (ACKR3), formerly CXCR7, is a class A GPCR that binds chemokines—most notably CXCL12—with high affinity but signals primarily through β-arrestin rather than G proteins, functioning as a scavenger/decoy receptor that shapes chemokine gradients and modulates signaling of other receptors such as CXCR4. Structural and biophysical studies show ACKR3 adopts active-like conformations biased toward arrestin coupling and lacks productive G protein engagement, with key conformational dynamics in transmembrane helices and arrestin-binding interfaces underlying this bias. Beyond chemokines, ACKR3 broadly scavenges endogenous opioid peptides in the CNS, reducing their availability to classical opioid receptors, and a selective competitor peptide (LIH383) can relieve this negative regulation to potentiate opioid receptor activity. ACKR3 is implicated in development (neuronal, cardiovascular), immune cell trafficking, cancer progression (including glioblastoma), and cardiovascular biology, and it is under active investigation as a therapeutic target with emerging peptide and small-molecule antagonists and agonists that modulate β-arrestin recruitment, receptor internalization, and ligand availability.

Other names

C-X-C chemokine receptor type 7 (CXCR7)RDC1 (historical/orphan receptor designation)GPR159 (rare, historical)

Antagonists/competitors (e.g., ACT-1004-1239, LIH383) inhibit ACKR3 scavenging and β-arrestin recruitment, potentially increasing availability of chemokines or opioid peptides to other receptors and modulating downstream signaling. Agonists (small molecules/peptides) promote β-arrestin recruitment, receptor internalization, and chemokine scavenging; can reduce prothrombotic markers (e.g., P-selectin expression) in experimental systems. Allosteric modulation of receptor conformations affecting arrestin bias and heterodimer effects with CXCR4.