Chemokine receptors are a family of structurally similar transmembrane proteins, each of which is selective for a specific ligand. Because the proteins need detergents to stabilize them, their binding properties are hard to study. Last year, Shuguang Zhang of the Massachusetts Institute of Technology and coworkers reported a QTY code that eliminates the need for detergents by replacing hydrophobic amino acids with structurally similar hydrophilic ones. The proteins become water-soluble even while maintaining their native structure, which simplifies analysis. Zhang, postdoc Rui Qing, and coworkers have now used the code to make and study the binding properties of five chemokine receptor QTY variants and chimeric chemokine receptors (Proc. Natl. Acad. Sci. U.S.A. 2019, DOI: 10.1073/pnas.1909026116). The researchers show that QTY chemokine receptors produced in Escherichia coli bind their native ligands with similar affinities as the native receptors. By combining a QTY version of the transmembrane portion of one chemokine receptor with the extracellular loops of another, the researchers made chimeric receptors. They determined that these chimeric receptors are better able to bind the ligand that goes with the extracellular loops than with the transmembrane domain. “We can now use one transmembrane domain receptor scaffold and append the other 20 kinds of chemokine receptor extracellular domains in order to systematically study how these receptors finely distinguish their ligands,” Zhang says. He adds that that the chimeric receptors may be useful as sensors with tunable ligand affinity.