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Structural basis of IL-23 antagonism by an Alphabody protein scaffold

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Abstract
Protein scaffolds can provide a promising alternative to antibodies for various biomedical and biotechnological applications, including therapeutics. Here we describe the design and development of the Alphabody, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold. We report affinity-matured Alphabodies with favourable physicochemical properties that can specifically neutralize human interleukin (IL)-23, a pivotal therapeutic target in autoimmune inflammatory diseases such as psoriasis and multiple sclerosis. The crystal structure of human IL-23 in complex with an affinity-matured Alphabody reveals how the variable interhelical groove of the scaffold uniquely targets a large epitope on the p19 subunit of IL-23 to harness fully the hydrophobic and hydrogen-bonding potential of tryptophan and tyrosine residues contributed by p19 and the Alphabody, respectively. Thus, Alphabodies are suitable for targeting protein-protein interfaces of therapeutic importance and can be tailored to interrogate desired design and binding-mode principles via efficient selection and affinity-maturation strategies.
Keywords
PSORIASIS, THERAPEUTIC PROTEINS, DOUBLE-BLIND, USTEKINUMAB, BINDING-PROTEINS, INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY, SIGNAL RECOGNITION PARTICLE, IL-12, AFFINITY, FEATURES

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MLA
Desmet, Johan et al. “Structural Basis of IL-23 Antagonism by an Alphabody Protein Scaffold.” NATURE COMMUNICATIONS 5 (2014): n. pag. Print.
APA
Desmet, Johan, Verstraete, K., Bloch, Y., Lorent, E., Wen, Y., Devreese, B., Vandenbroucke, K., et al. (2014). Structural basis of IL-23 antagonism by an Alphabody protein scaffold. NATURE COMMUNICATIONS, 5.
Chicago author-date
Desmet, Johan, Kenneth Verstraete, Yehudi Bloch, Eric Lorent, Yurong Wen, Bart Devreese, Karen Vandenbroucke, et al. 2014. “Structural Basis of IL-23 Antagonism by an Alphabody Protein Scaffold.” Nature Communications 5.
Chicago author-date (all authors)
Desmet, Johan, Kenneth Verstraete, Yehudi Bloch, Eric Lorent, Yurong Wen, Bart Devreese, Karen Vandenbroucke, Stefan Loverix, Thore Hettmann, Sabrina Deroo, Klaartje Somers, Paula Henderikx, Ignace Lasters, and Savvas Savvides. 2014. “Structural Basis of IL-23 Antagonism by an Alphabody Protein Scaffold.” Nature Communications 5.
Vancouver
1.
Desmet J, Verstraete K, Bloch Y, Lorent E, Wen Y, Devreese B, et al. Structural basis of IL-23 antagonism by an Alphabody protein scaffold. NATURE COMMUNICATIONS. 2014;5.
IEEE
[1]
J. Desmet et al., “Structural basis of IL-23 antagonism by an Alphabody protein scaffold,” NATURE COMMUNICATIONS, vol. 5, 2014.
@article{5869757,
  abstract     = {Protein scaffolds can provide a promising alternative to antibodies for various biomedical and biotechnological applications, including therapeutics. Here we describe the design and development of the Alphabody, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold. We report affinity-matured Alphabodies with favourable physicochemical properties that can specifically neutralize human interleukin (IL)-23, a pivotal therapeutic target in autoimmune inflammatory diseases such as psoriasis and multiple sclerosis. The crystal structure of human IL-23 in complex with an affinity-matured Alphabody reveals how the variable interhelical groove of the scaffold uniquely targets a large epitope on the p19 subunit of IL-23 to harness fully the hydrophobic and hydrogen-bonding potential of tryptophan and tyrosine residues contributed by p19 and the Alphabody, respectively. Thus, Alphabodies are suitable for targeting protein-protein interfaces of therapeutic importance and can be tailored to interrogate desired design and binding-mode principles via efficient selection and affinity-maturation strategies.},
  articleno    = {5237},
  author       = {Desmet, Johan and Verstraete, Kenneth and Bloch, Yehudi and Lorent, Eric and Wen, Yurong and Devreese, Bart and Vandenbroucke, Karen and Loverix, Stefan and Hettmann, Thore and Deroo, Sabrina and Somers, Klaartje and Henderikx, Paula and Lasters, Ignace and Savvides, Savvas},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  keywords     = {PSORIASIS,THERAPEUTIC PROTEINS,DOUBLE-BLIND,USTEKINUMAB,BINDING-PROTEINS,INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY,SIGNAL RECOGNITION PARTICLE,IL-12,AFFINITY,FEATURES},
  language     = {eng},
  pages        = {12},
  title        = {Structural basis of IL-23 antagonism by an Alphabody protein scaffold},
  url          = {http://dx.doi.org/10.1038/ncomms6237},
  volume       = {5},
  year         = {2014},
}

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