QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities

Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):E8652-E8659. doi: 10.1073/pnas.1811031115. Epub 2018 Aug 28.


Structure and function studies of membrane proteins, particularly G protein-coupled receptors and multipass transmembrane proteins, require detergents. We have devised a simple tool, the QTY code (glutamine, threonine, and tyrosine), for designing hydrophobic domains to become water soluble without detergents. Here we report using the QTY code to systematically replace the hydrophobic amino acids leucine, valine, isoleucine, and phenylalanine in the seven transmembrane α-helices of CCR5, CXCR4, CCR10, and CXCR7. We show that QTY code-designed chemokine receptor variants retain their thermostabilities, α-helical structures, and ligand-binding activities in buffer and 50% human serum. CCR5QTY, CXCR4QTY, and CXCR7QTY also bind to HIV coat protein gp41-120. Despite substantial transmembrane domain changes, the detergent-free QTY variants maintain stable structures and retain their ligand-binding activities. We believe the QTY code will be useful for designing water-soluble variants of membrane proteins and other water-insoluble aggregated proteins.

Keywords: GPCR; alpha-helix engineering; hydrophobic to hydrophilic; membrane proteins; protein design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amino Acids / chemistry
  • Amino Acids / genetics
  • Amino Acids / metabolism
  • Detergents / chemistry
  • Glutamine / chemistry
  • Glutamine / genetics
  • Glutamine / metabolism*
  • Hot Temperature
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Protein Binding
  • Protein Stability
  • Protein Structure, Secondary
  • Receptors, Chemokine / chemistry
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism*
  • Solubility
  • Threonine / chemistry
  • Threonine / genetics
  • Threonine / metabolism*
  • Tyrosine / chemistry
  • Tyrosine / genetics
  • Tyrosine / metabolism*
  • Water / chemistry


  • Amino Acids
  • Detergents
  • Ligands
  • Receptors, Chemokine
  • Water
  • Glutamine
  • Threonine
  • Tyrosine