7ZXK

Human IL-27 in complex with neutralizing SRF388 FAb fragment

Summary for 7ZXK

• Entry DOI: 10.2210/pdb7zxk/pdb
• Related: 7zg0
• Descriptor: Interleukin-27 subunit alpha, Interleukin-27 subunit beta, SRF388 Heavy Chain, ... (6 entities in total)
• Functional Keywords: cytokine, heterodimer, neutralizing, antibody
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 192673.51

Authors

Bloch, Y.,Skladanowska, K.,Strand, J.,Welin, M.,Logan, D.,Hill, J.,Savvides, S.N. (deposition date: 2022-05-21, release date: 2022-11-02, Last modification date: 2024-11-06)

Primary citation

Skladanowska, K.,Bloch, Y.,Strand, J.,White, K.F.,Hua, J.,Aldridge, D.,Welin, M.,Logan, D.T.,Soete, A.,Merceron, R.,Murphy, C.,Provost, M.,Bazan, J.F.,Hunter, C.A.,Hill, J.A.,Savvides, S.N.
Structural basis of activation and antagonism of receptor signaling mediated by interleukin-27.
Cell Rep, 41:111490-111490, 2022

PubMed Abstract: Interleukin-27 (IL-27) uniquely assembles p28 and EBI3 subunits to a heterodimeric cytokine that signals via IL-27Rα and gp130. To provide the structural framework for receptor activation by IL-27 and its emerging therapeutic targeting, we report here crystal structures of mouse IL-27 in complex with IL-27Rα and of human IL-27 in complex with SRF388, a monoclonal antibody undergoing clinical trials with oncology indications. One face of the helical p28 subunit interacts with EBI3, while the opposite face nestles into the interdomain elbow of IL-27Rα to juxtapose IL-27Rα to EBI3. This orients IL-27Rα for paired signaling with gp130, which only uses its immunoglobulin domain to bind to IL-27. Such a signaling complex is distinct from those mediated by IL-12 and IL-23. The SRF388 binding epitope on IL-27 overlaps with the IL-27Rα interaction site explaining its potent antagonistic properties. Collectively, our findings will facilitate the mechanistic interrogation, engineering, and therapeutic targeting of IL-27.

PubMed: 36261006
DOI: 10.1016/j.celrep.2022.111490

Experimental method

X-RAY DIFFRACTION (2.2 Å)