The G protein coupled receptor CXCR4 designed by the QTY code becomes more hydrophilic and retains cell signaling activity

Tegler, Lotta T.; Corin, Karolina; Pick, Horst; Brookes, Jennifer C.; Skuhersky, Michael; Vogel, Horst; Zhang, Shuguang

doi:10.1038/s41598-020-77659-x

Cited by 15 publications

(30 citation statements)

References 38 publications

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“…The QTY changes hydrophobic 6TM-12TM into hydrophilic 6TM-12TM, without, however, signi cantly changing the alpha-helical molecular structures, as shown in Figure 3. Analogous reproducible experimental results reported for chemokine and cytokine receptors in our previous publications 31,32,33,34,35 . However, our experimental results showed that the structure integrity, stability, and ligand-binding activities have been retained from the water-soluble QTYvariant chemokine receptors and cytokine receptors 31,32,33,34,35 .…”

Section: Superposition Of Native Transporters and Their Water-soluble...supporting

confidence: 88%

“…On 15 July 2021, Google DeepMind announced the AlphaFold2, and at the same time David Baker's lab introduced RoseTTAFold as machine learning revolutionary tool for the very accurate prediction of protein structures 28,29,30 We previously applied the QTY (Glutamine, Threonine, Tyrosine) code to design several detergent-free transmembrane (TM) protein chemokine receptors and cytokine receptors for various uses using conventional computing programs to simulate several G protein-coupled receptors. Each took ~ 5 weeks to complete the simulation 33,34,35 . The expressed and puri ed water-soluble proteins exhibited predicted characteristics and retained ligand-binding activity 31,32,33,34,35 .…”

Section: Introductionmentioning

confidence: 99%

“…Each took ~ 5 weeks to complete the simulation 33,34,35 . The expressed and puri ed water-soluble proteins exhibited predicted characteristics and retained ligand-binding activity 31,32,33,34,35 . In July 2021, we prepared QTY variant protein structure predictions using AlphaFold2, achieving better results in 1-2 hours 36, 37 , rather than ~ 5 weeks for each molecular simulation using GOMoDo, AMBER and YASARA programs 31,32,33 .…”

Section: Introductionmentioning

confidence: 99%

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Study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants

Smorodina

Diankin

Tao

et al. 2022

Preprint

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Solute carrier transporters are integral membrane proteins, and are important for diverse cellular nutrient transports, metabolism, energy demand, and other vital biological activities. They have recently been implicated in pancreatic cancer and other cancer metastasis, angiogenesis, programmed cell death and proliferation, cell metabolism and chemo-sensitivity. Here we report the study of 13 human solute carrier membrane transporters using the highly accurate AlphaFold2 predictions of 3D protein structures. In the native structures, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F) in the transmembrane alpha-helices. These hydrophobic amino acids L, I, V, F are systematically replaced by hydrophilic amino acids glutamine (Q), threonine (T) and tyrosine (Y), thus the QTY code. Therefore, these QTY variant transporters become water-soluble without requiring detergents. We present the superposed structures of these native solute carrier transporters and their water-soluble QTY variants. The superposed structures show remarkable similarity with RMSD ~1Å-4Å despite >46% protein sequence substitutions in transmembrane alpha-helices. We also show the differences of surface hydrophobicity between the native solute carrier transporters and their QTY variants. Our study may further stimulate designs of water-soluble transmembrane proteins and other aggregated proteins for drug discovery and biotechnological applications.

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Section: Superposition Of Native Transporters and Their Water-soluble...supporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants

Smorodina

Diankin

Tao

et al. 2022

Preprint

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“…In a recent paper, Tegler et al described an early attempt in the development of the QTY code, where only 29 lipid-facing residues in CXCR4 were substituted, named as CXCR4 QTY29 . 280 The design provided a middle ground for QTY-based redesign where the receptor became more hydrophilic than the native protein, but still required detergent to stabilize in aqueous solution. It retained partial membrane-based functions.…”

Section: Qty Codementioning

confidence: 99%

Protein Design: From the Aspect of Water Solubility and Stability

et al. 2022

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Water solubility and structural stability are key merits for proteins defined by the primary sequence and 3D-conformation. Their manipulation represents important aspects of the protein design field that relies on the accurate placement of amino acids and molecular interactions, guided by underlying physiochemical principles. Emulated designer proteins with well-defined properties both fuel the knowledge-base for more precise computational design models and are used in various biomedical and nanotechnological applications. The continuous developments in protein science, increasing computing power, new algorithms, and characterization techniques provide sophisticated toolkits for solubility design beyond guess work. In this review, we summarize recent advances in the protein design field with respect to water solubility and structural stability. After introducing fundamental design rules, we discuss the transmembrane protein solubilization and de novo transmembrane protein design. Traditional strategies to enhance protein solubility and structural stability are introduced. The designs of stable protein complexes and high-order assemblies are covered. Computational methodologies behind these endeavors, including structure prediction programs, machine learning algorithms, and specialty software dedicated to the evaluation of protein solubility and aggregation, are discussed. The findings and opportunities for Cryo-EM are presented. This review provides an overview of significant progress and prospects in accurate protein design for solubility and stability.

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“…The QTY code was initially applied to convert transmembrane (TM) α -helices of seven G protein-coupled receptors (GPCRs), namely the chemokine receptors CCR5, CCR9, CCR10, CXCR2, CXCR4, CXCR5, CXCR7 (Zhang et al ., 2018 a , 2018 b ; Qing et al ., 2019; Hao et al ., 2020; Tegler et al ., 2020; Skuhersky et al ., 2021; Tao et al ., 2022). Despite ~20–30% overall amino acid changes (46–58% transmembrane domain amino acid changes), these water-soluble QTY variant receptors still retained their overall structure, with a similar amount of α -helical content, and folded into stable proteins (Fig.…”

Section: Conversion Of a Hydrophobic α-Helix To A Hydrophilic α-Helix...mentioning

confidence: 99%

Hiding in plain sight: three chemically distinctα-helix types

Zhang

Egli

2022

Quart. Rev. Biophys.

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Linus Pauling in 1950 published a three-dimensional model for a universal protein secondary structure motif which he initially called the alpha-spiral. Jack Dunitz, then a postdoc in Pauling's lab suggested to Pauling that the term helix is more accurate than spiral when describing the right-handed peptide and protein coiled structures. Pauling agreed, hence the rise of the alpha-helix, and, by extension, the 'double helix' structure of DNA. Although structural biologists and protein chemists are familiar with varying polar and apolar characters of amino acids in alpha-helices, to non-experts the three chemically distinct alphahelix types classified here may hide in plain sight.

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The G protein coupled receptor CXCR4 designed by the QTY code becomes more hydrophilic and retains cell signaling activity

Cited by 15 publications

References 38 publications

Study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants

Study of determined and AlphaFold2 predicted molecular structures of 13 human solute carrier transporters and their water-soluble QTY variants

Protein Design: From the Aspect of Water Solubility and Stability

Hiding in plain sight: three chemically distinctα-helix types

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