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De Novo-Designed α-Helical Barrels as Receptors for Small Molecules.

Thomas F, Dawson WM, Lang EJM, Burton AJ, Bartlett GJ, Rhys GG, Mulholland AJ, Woolfson DN
ACS Synth Biol 7 1808-1816 (2018)
Cited: 27 times
EuropePMC logo PMID: 29944338

Abstract

We describe de novo-designed α-helical barrels (αHBs) that bind and discriminate between lipophilic biologically active molecules. αHBs have five or more α-helices arranged around central hydrophobic channels the diameters of which scale with oligomer state. We show that pentameric, hexameric, and heptameric αHBs bind the environmentally sensitive dye 1,6-diphenylhexatriene (DPH) in the micromolar range and fluoresce. Displacement of the dye is used to report the binding of nonfluorescent molecules: palmitic acid and retinol bind to all three αHBs with submicromolar inhibitor constants; farnesol binds the hexamer and heptamer; but β-carotene binds only the heptamer. A co-crystal structure of the hexamer with farnesol reveals oriented binding in the center of the hydrophobic channel. Charged side chains engineered into the lumen of the heptamer facilitate binding of polar ligands: a glutamate variant binds a cationic variant of DPH, and introducing lysine allows binding of the biosynthetically important farnesol diphosphate.

Reviews citing this publication (5)

  1. Protein Design: From the Aspect of Water Solubility and Stability. Qing R, Hao S, Smorodina E, Jin D, Zalevsky A, Zhang S. Chem Rev 122 14085-14179 (2022)
  2. De Novo Designed α-Helical Coiled-Coil Peptides as Scaffolds for Chemical Reactions. Rink WM, Thomas F. Chemistry 25 1665-1677 (2019)
  3. Recent Progress Using De Novo Design to Study Protein Structure, Design and Binding Interactions. Ferrando J, Solomon LA. Life (Basel) 11 225 (2021)
  4. Understanding a protein fold: The physics, chemistry, and biology of α-helical coiled coils. Woolfson DN. J Biol Chem 299 104579 (2023)
  5. A Structural Analysis of Proteinaceous Nanotube Cavities and Their Applications in Nanotechnology. Heide F, Stetefeld J. Nanomaterials (Basel) 12 4080 (2022)

Articles citing this publication (22)

  1. A defined structural unit enables de novo design of small-molecule-binding proteins. Polizzi NF, DeGrado WF. Science 369 1227-1233 (2020)
  2. Dual self-assembly of supramolecular peptide nanotubes to provide stabilisation in water. Rho JY, Cox H, Mansfield EDH, Ellacott SH, Peltier R, Brendel JC, Hartlieb M, Waigh TA, Perrier S. Nat Commun 10 4708 (2019)
  3. Orthogonal fluorescent chemogenetic reporters for multicolor imaging. Tebo AG, Moeyaert B, Thauvin M, Carlon-Andres I, Böken D, Volovitch M, Padilla-Parra S, Dedecker P, Vriz S, Gautier A. Nat Chem Biol 17 30-38 (2021)
  4. Coiled coils 9-to-5: rational de novo design of α-helical barrels with tunable oligomeric states. Dawson WM, Martin FJO, Rhys GG, Shelley KL, Brady RL, Woolfson DN. Chem Sci 12 6923-6928 (2021)
  5. Controlled Lengthwise Assembly of Helical Peptide Nanofibers to Modulate CD8+ T-Cell Responses. Fries CN, Wu Y, Kelly SH, Wolf M, Votaw NL, Zauscher S, Collier JH. Adv Mater 32 e2003310 (2020)
  6. Improving the Efficiency of Ligand-Binding Protein Design with Molecular Dynamics Simulations. Barros EP, Schiffer JM, Vorobieva A, Dou J, Baker D, Amaro RE. J Chem Theory Comput 15 5703-5715 (2019)
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  8. Structural resolution of switchable states of a de novo peptide assembly. Dawson WM, Lang EJM, Rhys GG, Shelley KL, Williams C, Brady RL, Crump MP, Mulholland AJ, Woolfson DN. Nat Commun 12 1530 (2021)
  9. From peptides to proteins: coiled-coil tetramers to single-chain 4-helix bundles. Naudin EA, Albanese KI, Smith AJ, Mylemans B, Baker EG, Weiner OD, Andrews DM, Tigue N, Savery NJ, Woolfson DN. Chem Sci 13 11330-11340 (2022)
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  11. On the Catalytic Activity of the Engineered Coiled-Coil Heptamer Mimicking the Hydrolase Enzymes: Insights from a Computational Study. Prejanò M, Romeo I, Russo N, Marino T. Int J Mol Sci 21 E4551 (2020)
  12. Charge transfer as a mechanism for chlorophyll fluorescence concentration quenching. Bourne-Worster S, Feighan O, Manby FR. Proc Natl Acad Sci U S A 120 e2210811120 (2023)
  13. An enhanced activity and thermostability of chimeric Bst DNA polymerase for isothermal amplification applications. Li J, Li Y, Li Y, Ma Y, Xu W, Wang J. Appl Microbiol Biotechnol 107 6527-6540 (2023)
  14. Differential sensing with arrays of de novo designed peptide assemblies. Dawson WM, Shelley KL, Fletcher JM, Scott DA, Lombardi L, Rhys GG, LaGambina TJ, Obst U, Burton AJ, Cross JA, Davies G, Martin FJO, Wiseman FJ, Brady RL, Tew D, Wood CW, Woolfson DN. Nat Commun 14 383 (2023)
  15. Hollow Octadecameric Self-Assembly of Collagen-like Peptides. Yu LT, Hancu MC, Kreutzberger MAB, Henrickson A, Demeler B, Egelman EH, Hartgerink JD. J Am Chem Soc 145 5285-5296 (2023)
  16. Identification of novel functional mini-receptors by combinatorial screening of split-WW domains. Neitz H, Paul NB, Häge FR, Lindner C, Graebner R, Kovermann M, Thomas F. Chem Sci 13 9079-9090 (2022)
  17. A curcumin direct protein biosensor for cell-free prototyping. Kennedy A, Griffin G, Freemont PS, Polizzi KM, Moore SJ. Eng Biol 6 62-68 (2022)
  18. An abiotic, tetrameric, eight-helix bundle. Menke FS, Wicher B, Allmendinger L, Maurizot V, Huc I. Chem Sci 14 3742-3751 (2023)
  19. Computational design of a sensitive, selective phase-changing sensor protein for the VX nerve agent. McCann JJ, Pike DH, Brown MC, Crouse DT, Nanda V, Koder RL. Sci Adv 8 eabh3421 (2022)
  20. Metal-Promoted Higher-Order Assembly of Disulfide-Stapled Helical Barrels. Agrahari A, Lipton M, Chmielewski J. Nanomaterials (Basel) 13 2645 (2023)
  21. Segmentation strategy of de novo designed four-helical bundles expands protein oligomerization modalities for cell regulation. Merljak E, Malovrh B, Jerala R. Nat Commun 14 1995 (2023)
  22. Self-assembly of cyclic peptide monolayers by hydrophobic supramolecular hinges. Insua I, Cardellini A, Díaz S, Bergueiro J, Capelli R, Pavan GM, Montenegro J. Chem Sci 14 14074-14081 (2023)


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