5MJ4

INTERLEUKIN-23 COMPLEX WITH AN ANTAGONISTIC ALPHABODY, CRYSTAL FORM 2

Replaces:  4OG9

Summary for 5MJ4

• Entry DOI: 10.2210/pdb5mj4/pdb
• Related: 5MJ3
• Descriptor: Interleukin-12 subunit beta, Interleukin-23 subunit alpha, ALPHABODY MA12, ... (4 entities in total)
• Functional Keywords: single-chain antiparallel triple-helix coiled-coil, immunoglobulin-like, 4-alpha helical bundle, antagonist, n-linked glycosylation, cytokine-antagonist complex, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 67351.65

Authors

Desmet, J.,Verstraete, K.,Bloch, Y.,Lorent, E.,Wen, Y.,Devreese, B.,Vandenbroucke, K.,Loverix, S.,Hettmann, T.,Deroo, S.,Somers, K.,Henderikx, P.,Lasters, I.,Savvides, S. (deposition date: 2016-11-29, release date: 2017-01-11, Last modification date: 2024-10-23)

Primary citation

Desmet, J.,Verstraete, K.,Bloch, Y.,Lorent, E.,Wen, Y.,Devreese, B.,Vandenbroucke, K.,Loverix, S.,Hettmann, T.,Deroo, S.,Somers, K.,Henderikx, P.,Lasters, I.,Savvides, S.
STRUCTURAL BASIS OF IL-23 ANTAGONISM BY AN ALPHABODY PROTEIN
Nature Communications, 5:5237-, 2014

PubMed 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.

PubMed: 25354530
DOI: 10.1038/NCOMMS6237

Experimental method

X-RAY DIFFRACTION (3.4 Å)