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

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

Author information

1
Center for Bits and Atoms, Massachusetts Institute of Technology, Cambridge, MA 02139; shuguang@mit.edu.
2
Center for Bits and Atoms, Massachusetts Institute of Technology, Cambridge, MA 02139.
3
State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiaotong University, 200240 Shanghai, China.
4
Next Interactions, Inc., Richmond, CA 94806.
5
2bind GmbH, 93053 Regensburg, Germany.
6
Centre for Structural Systems Biology, Research Center Juelich, D-22607 Hamburg, Germany.
7
Cube Biotech, GmbH, 40789 Monheim, Germany.

Abstract

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

PMID:
30154163
PMCID:
PMC6140526
DOI:
10.1073/pnas.1811031115
[Indexed for MEDLINE]
Free PMC Article

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