Conformational dynamics underlying atypical chemokine receptor 3 activation

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• Atypical Chemokine Receptor 3 (ACKR3) is a G protein-coupled receptor lacking canonical G protein signaling.
• The structural basis for ACKR3's functional selectivity and dynamic activation remains unclear.

Purpose of the Study:

• To elucidate the binding mode and mechanism of action for ACKR3 ligands with varying efficacies.
• To investigate the structural dynamics governing ACKR3 activation and β-arrestin 1 interaction.

Main Methods:

• Hydrogen/deuterium exchange mass spectrometry (HDX-MS).
• Site-directed mutagenesis.
• Molecular dynamics (MD) simulations.

Main Results:

• Ligand binding and ACKR3 activation/inhibition are regulated by conformational shifts in intracellular helix 6, loop 2, and helix 7.
• The DRY motif is protected during both activation and inhibition.
• Identified ACKR3 ligand binding sites and allosteric modulation by β-arrestin 1.

Conclusions:

• ACKR3 exhibits atypical dynamics, explaining its G protein signaling deficiency.
• Structure-function relationships of ACKR3 small molecule ligands are elucidated.
• The binding mode and allosteric effects of β-arrestin 1 on ACKR3 are characterized.