6O4P

The crystal structure of the interleukin 11 alpha receptor

Summary for 6O4P

• Entry DOI: 10.2210/pdb6o4p/pdb
• Descriptor: Interleukin-11 receptor subunit alpha, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: cytokine, interleukin, receptor, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 78874.29

Authors

Aizel, K.,Metcalfe, R.D.,Griffin, M.D.W. (deposition date: 2019-02-28, release date: 2020-05-06, Last modification date: 2024-11-20)

Primary citation

Metcalfe, R.D.,Aizel, K.,Zlatic, C.O.,Nguyen, P.M.,Morton, C.J.,Lio, D.S.,Cheng, H.C.,Dobson, R.C.J.,Parker, M.W.,Gooley, P.R.,Putoczki, T.L.,Griffin, M.D.W.
The structure of the extracellular domains of human interleukin 11 alpha receptor reveals mechanisms of cytokine engagement.
J.Biol.Chem., 295:8285-8301, 2020

PubMed Abstract: Interleukin (IL) 11 activates multiple intracellular signaling pathways by forming a complex with its cell surface α-receptor, IL-11Rα, and the β-subunit receptor, gp130. Dysregulated IL-11 signaling has been implicated in several diseases, including some cancers and fibrosis. Mutations in IL-11Rα that reduce signaling are also associated with hereditary cranial malformations. Here we present the first crystal structure of the extracellular domains of human IL-11Rα and a structure of human IL-11 that reveals previously unresolved detail. Disease-associated mutations in IL-11Rα are generally distal to putative ligand-binding sites. Molecular dynamics simulations showed that specific mutations destabilize IL-11Rα and may have indirect effects on the cytokine-binding region. We show that IL-11 and IL-11Rα form a 1:1 complex with nanomolar affinity and present a model of the complex. Our results suggest that the thermodynamic and structural mechanisms of complex formation between IL-11 and IL-11Rα differ substantially from those previously reported for similar cytokines. This work reveals key determinants of the engagement of IL-11 by IL-11Rα that may be exploited in the development of strategies to modulate formation of the IL-11-IL-11Rα complex.

PubMed: 32332100
DOI: 10.1074/jbc.RA119.012351

Experimental method

X-RAY DIFFRACTION (3.429 Å)