6NCU

Interleukin-37 residues 53-206- dimer

Summary for 6NCU

• Entry DOI: 10.2210/pdb6ncu/pdb
• Descriptor: Interleukin-37 (1 entity in total)
• Functional Keywords: inflammation, interleukin, cytokine, innate immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 34625.77

Authors

Eisenmesser, E.Z. (deposition date: 2018-12-12, release date: 2019-03-13, Last modification date: 2024-04-24)

Primary citation

Eisenmesser, E.Z.,Gottschlich, A.,Redzic, J.S.,Paukovich, N.,Nix, J.C.,Azam, T.,Zhang, L.,Zhao, R.,Kieft, J.S.,The, E.,Meng, X.,Dinarello, C.A.
Interleukin-37 monomer is the active form for reducing innate immunity.
Proc. Natl. Acad. Sci. U.S.A., 116:5514-5522, 2019

PubMed Abstract: Interleukin-37 (IL-37), a member of the IL-1 family of cytokines, is a fundamental suppressor of innate and acquired immunities. Here, we used an integrative approach that combines biophysical, biochemical, and biological studies to elucidate the unique characteristics of IL-37. Our studies reveal that single amino acid mutations at the IL-37 dimer interface that result in the stable formation of IL-37 monomers also remain monomeric at high micromolar concentrations and that these monomeric IL-37 forms comprise higher antiinflammatory activities than native IL-37 on multiple cell types. We find that, because native IL-37 forms dimers with nanomolar affinity, higher IL-37 only weakly suppresses downstream markers of inflammation whereas lower concentrations are more effective. We further show that IL-37 is a heparin binding protein that modulates this self-association and that the IL-37 dimers must block the activity of the IL-37 monomer. Specifically, native IL-37 at 2.5 nM reduces lipopolysaccharide (LPS)-induced vascular cell adhesion molecule (VCAM) protein levels by ∼50%, whereas the monomeric D73K mutant reduced VCAM by 90% at the same concentration. Compared with other members of the IL-1 family, both the N and the C termini of IL-37 are extended, and we show they are disordered in the context of the free protein. Furthermore, the presence of, at least, one of these extended termini is required for IL-37 suppressive activity. Based on these structural and biological studies, we present a model of IL-37 interactions that accounts for its mechanism in suppressing innate inflammation.

PubMed: 30819901
DOI: 10.1073/pnas.1819672116

Experimental method

X-RAY DIFFRACTION (3.5 Å)