QTY code designed thermostable and water-soluble chimeric chemokine receptors with tunable ligand affinity

Significance There are 20 chemokine receptors that bind their respective chemokines. It is not currently understood how these structurally similar receptors distinguish their ligands; namely, how EC loops and transmembrane domains of these receptors are involved in ligand-binding activities. With the detergent-free GPCRs, we show that it is now possible to design and produce chimeric receptor proteins to study ligand-binding mechanisms. We exchanged the N terminus and 3 EC loops of natural chemokine receptor CXCR4 to append them onto the 7TM α-helices of detergent-free variant CCR5 QTY , and systematically studied which ligands it binds. These designer chimeric receptors provide insight into how natural receptors bind their respective ligands. These chimeric receptors with tunable functionality may have applications for bioelectronics sensing devices.