Structural basis of IL-23 antagonism by an Alphabody protein scaffold
| Autor: | Karen Vandenbroucke, Savvas N. Savvides, Bart Devreese, Klaartje Somers, Johan Desmet, Yurong Wen, Yehudi Bloch, Paula Henderikx, Thore Hettmann, Stefan Loverix, Kenneth Verstraete, Ignace Lasters, Eric Lorent, Sabrina Deroo |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Scaffold protein
SIGNAL RECOGNITION PARTICLE Male Scaffold USTEKINUMAB Protein subunit FEATURES Molecular Sequence Data Drug Evaluation Preclinical General Physics and Astronomy Computational biology Biology Bioinformatics DNA-binding protein BINDING-PROTEINS Interleukin-23 General Biochemistry Genetics and Molecular Biology Epitope Article Cell Line 03 medical and health sciences DOUBLE-BLIND Mice 0302 clinical medicine Animals Humans Psoriasis Amino Acid Sequence Tyrosine Peptide sequence 030304 developmental biology INTERLEUKIN-12/23 MONOCLONAL-ANTIBODY AFFINITY 0303 health sciences Multidisciplinary PSORIASIS Biology and Life Sciences General Chemistry 3. Good health Mice Inbred C57BL IL-12 030220 oncology & carcinogenesis THERAPEUTIC PROTEINS Alphabody ddc:500 Peptides |
| Zdroj: | Nature Communications 'Nature Communications ', vol: 5, pages: 5237-1-5237-12 (2014) NATURE COMMUNICATIONS Nature Communications 5, 5237 (20142014). doi:10.1038/ncomms6237 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms6237 |
| Popis: | 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. Protein scaffolds can serve as alternatives to antibodies in a range of applications. Here, the authors report the design and development of Alphabody™, a protein scaffold featuring a single-chain antiparallel triple-helix coiled-coil fold that the authors use to develop Alphabodies that can neutralize human IL-23 with high specificity and affinity. |
| Databáze: | OpenAIRE |
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