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Zarzycka, B.

Publications and source records attributed to Zarzycka, B..

2 recordsLinked to original sources
bioRxiv2024

Design, synthesis and pharmacological characterization of the first photoswitchable small-molecule agonist for the Atypical Chemokine Receptor 3

1.Photopharmacology offers the promise of optical modulation of cellular signaling in a spatially and temporally controlled fashion with light-sensitive molecules. This study presents the first small-molecule photoswitchable agonist for an atypical G protein-coupled receptor (GPCR), the atypical chemokine receptor 3 (ACKR3). Inspired by a known benzylpiperidine-based ACKR3 agonist scaffold, 12 photoswitchable azobenzene-containing analogs were synthesized and characterized for their interaction with ACKR3. After analysis of Structure-Photochemistry and Structure-Affinity Relationships (SAR), compound 3e was selected as the best photoswitchable ACKR3 agonist in the series. Compound 3e can be effectively switched from its thermodynamically stable trans state to the less active cis-isomer with a PhotoStationary State of 96 %. The thermodynamically less stable cis-3e only slowly switches back to the trans state (t1/2,37 {degrees}C = 15 days), and trans-3e binds and activates ACKR3 at 10-fold lower concentrations compared to its cis-isomer. Compound 3e demonstrates selectivity for ACKR3 within in a panel of chemokine receptors. Using the recently published ACKR3 cryo-EM structures in computational studies, a binding mode for trans-3e is proposed and is perfectly in line with the observed SAR and the loss of interaction with ACKR3 upon photoswitching. ACKR3 agonist 3e (VUF25471) is the first photoswitchable ligand for an atypical GPCR and will be a useful tool to investigate the role of ACKR3 in biological settings.

pharmacology and toxicology↗
bioRxiv2023

Conformational dynamics underlying Atypical Chemokine Receptor 3 activation

Atypical Chemokine Receptor 3 (ACKR3) is a G protein-coupled receptor that does not signal through G proteins. It is known as a chemokine scavenger involved in various pathologies, making it an appealing yet intriguing therapeutic target. Indeed, the structural properties that govern ACKR3 functional selectivity and the overall conformational dynamics of ACKR3 activation are poorly understood. Here we combined Hydrogen/Deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics simulations to examine the binding mode and mechanism of action of various small-molecule ACKR3 ligands of different efficacy for {beta}-arrestin recruitment. Our results show that activation or inhibition of ACKR3 is largely governed by intracellular conformational changes of helix 6, intracellular loop 2 and helix 7, while the DRY motif becomes protected during both processes. Moreover, HDX-MS identifies the binding sites and the allosteric modulation of ACKR3 upon {beta}-arrestin 1 binding. In summary, this study highlights the structure-function relationship of small-molecule ligands, the overall activation dynamics of ACKR3, the binding mode of {beta}-arrestin 1 and the atypical dynamic features in ACKR3 that may contribute to its inability to activate G proteins.

biochemistry↗