8C3U

Crystal Structure of human IL-1beta in complex with a low molecular weight antagonist

Summary for 8C3U

• Entry DOI: 10.2210/pdb8c3u/pdb
• Descriptor: Interleukin-1 beta, (S)-4'-hydroxy-3'-(6-methyl-2-oxo-3-(1H-pyrazol-4-yl)indolin-3-yl)-[1,1'-biphenyl]-2,4-dicarboxylic acid (3 entities in total)
• Functional Keywords: beta trefoil fold; secreted, cytokine
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 35730.56

Authors

Rondeau, J.-M.,Lehmann, S.,Koch, E. (deposition date: 2022-12-28, release date: 2023-09-13, Last modification date: 2024-03-27)

Primary citation

Hommel, U.,Hurth, K.,Rondeau, J.M.,Vulpetti, A.,Ostermeier, D.,Boettcher, A.,Brady, J.P.,Hediger, M.,Lehmann, S.,Koch, E.,Blechschmidt, A.,Yamamoto, R.,Tundo Dottorello, V.,Haenni-Holzinger, S.,Kaiser, C.,Lehr, P.,Lingel, A.,Mureddu, L.,Schleberger, C.,Blank, J.,Ramage, P.,Freuler, F.,Eder, J.,Bornancin, F.
Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1 beta.
Nat Commun, 14:5497-5497, 2023

PubMed Abstract: Human interleukin-1β (hIL-1β) is a pro-inflammatory cytokine involved in many diseases. While hIL-1β directed antibodies have shown clinical benefit, an orally available low-molecular weight antagonist is still elusive, limiting the applications of hIL-1β-directed therapies. Here we describe the discovery of a low-molecular weight hIL-1β antagonist that blocks the interaction with the IL-1R1 receptor. Starting from a low affinity fragment-based screening hit 1, structure-based optimization resulted in a compound (S)-2 that binds and antagonizes hIL-1β with single-digit micromolar activity in biophysical, biochemical, and cellular assays. X-ray analysis reveals an allosteric mode of action that involves a hitherto unknown binding site in hIL-1β encompassing two loops involved in hIL-1R1/hIL-1β interactions. We show that residues of this binding site are part of a conformationally excited state of the mature cytokine. The compound antagonizes hIL-1β function in cells, including primary human fibroblasts, demonstrating the relevance of this discovery for future development of hIL-1β directed therapeutics.

PubMed: 37679328
DOI: 10.1038/s41467-023-41190-0

Experimental method

X-RAY DIFFRACTION (1.945 Å)