4GAF

Crystal structure of EBI-005, a chimera of human IL-1beta and IL-1Ra, bound to human Interleukin-1 receptor type 1

Summary for 4GAF

• Entry DOI: 10.2210/pdb4gaf/pdb
• Related: 4GAI
• Descriptor: EBI-005, Interleukin-1 receptor type 1, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: il-1beta, il-1ra, il-1r1, il-1 signaling, beta-trefoil, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 55368.89

Authors

Hou, J.,Townson, S.A.,Kovalchin, J.T.,Masci, A.,Kiner, O.,Shu, Y.,King, B.,Thomas, C.,Garcia, K.C.,Furfine, E.S.,Barnes, T.M. (deposition date: 2012-07-25, release date: 2013-02-20, Last modification date: 2024-10-16)

Primary citation

Hou, J.,Townson, S.A.,Kovalchin, J.T.,Masci, A.,Kiner, O.,Shu, Y.,King, B.M.,Schirmer, E.,Golden, K.,Thomas, C.,Garcia, K.C.,Zarbis-Papastoitsis, G.,Furfine, E.S.,Barnes, T.M.
Design of a superior cytokine antagonist for topical ophthalmic use.
Proc.Natl.Acad.Sci.USA, 110:3913-3918, 2013

PubMed Abstract: IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1β and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an ∼100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other β-trefoil family proteins in the IL-1 and FGF families.

PubMed: 23431173
DOI: 10.1073/pnas.1217996110

Experimental method

X-RAY DIFFRACTION (2.15 Å)