In collaboration with Prof. Horst Vogel and Dr. Horst Pick (EPFL, Lausanne, Switzerland).
G protein-coupled receptors (GPCRs) are vital for diverse biological functions, including vision, smell, and aging. They are also involved in a wide range of diseases, and are among the most important targets of medicinal drugs. Tools that facilitate GPCR studies or GPCR-based technologies or therapies are thus critical to develop. We used QTY code (glutamine, threonine, tyrosine) to systematically replace 29 membrane-facing leucine (L), isoleucine (I), valine (V), and phenylalanine (F) residues in the transmembrane alpha-helices of the GPCR CXCR4. This variant, CXCR4QTY29, became more water-soluble, while retaining the ability to bind its natural ligand CXCL12. When transfected CXCR4QTY29 gene into HEK293 cells, the translated CXCR4QTY29 receptor inserted into the cell membrane and retained its cellular signaling activity. This QTY code can significantly improve GPCR and membrane protein studies by making it possible to design functional hydrophilic receptors. The QTY code can be applied to diverse a-helical transmembrane proteins, and may aid in the development of other applications, including clinical therapies.