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

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.

journal_name

Nat Commun

journal_title

Nature communications

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 SN

doi

10.1038/ncomms6237

subject

Has Abstract

pub_date

2014-10-30 00:00:00

pages

5237

issn

2041-1723

pii

ncomms6237

journal_volume

5

pub_type

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