Effects of Small Molecule Ligands on ACKR3 ReceptorsS

Chemokines such as stromal derived factor 1 and their G pro-tein coupled receptors are well-known regulators of the devel-opment and functions of numerous tissues. C-X-C motif chemokine ligand 12 (CXCL12) has two receptors: C-X-C che-mokine motif receptor 4 (CXCR4) and atypical chemokine re-ceptor 3 (ACKR3). ACKR3 has been described as an atypical biased receptor because it does not appear to signal through G proteins and, instead, signals solely through the fl-arrestin pathway. In support of this conclusion, we have shown that ACKR3 is unable to signal through any of the known mamma-lian Ga isoforms and have generated a comprehensive map of the Ga activation by CXCL12/CXCR4. We also synthesized a series of small molecule ligands which acted as selective ago-nists for ACKR3 as assessed by their ability to recruit fl-arrestin to the receptor. Using select point mutations, we studied the molecular characteristics that determine the ability of small molecules to activate ACKR3 receptors, revealing a key role for the deeper binding pocket composed of residues in the trans-membrane domains of ACKR3. The development of more se-lective ACKR3 ligands should allow us to better appreciate the unique roles of ACKR3 in the CXCL12/CXCR4/ACKR3-signal-ing axis and better understand the structural determinants for ACKR3 activation.SIGNIFICANCE STATEMENT We are interested in the signaling produced by the G protein coupled receptor atypical chemokine receptor 3 (ACKR3), which signals atypically. In this study, novel selective ligands for ACKR3 were discovered and the site of interactions be-tween these small molecules and ACKR3 was defined. This work will help to better understand the unique signaling roles of ACKR3.

Automated summary

In this study, novel selective ligands for ACKR3 were discovered and the site of interactions between these small molecules and ACKR3 was defined. This work will help to better understand the unique signaling roles of ACKR3.