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

Proceedings of the National Academy of Sciences of the United States of America
Shuguang ZhangBarbara Maertens

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.

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Citations

Apr 17, 2019·BioTechniques·Joseph Martin, Abigail Sawyer
Nov 30, 2019·Proceedings of the National Academy of Sciences of the United States of America·Rui QingShuguang Zhang
Sep 18, 2020·Protein Science : a Publication of the Protein Society·Shuguang Zhang
Jul 17, 2021·Journal of Molecular Biology·Anastassia Andreevna Vorobieva
Jul 28, 2021·The Journal of Physical Chemistry. B·Chien-Lun HungYun-Wei Chiang

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