SNAP output for PDB entry 4ni7 [SNAP web server]

PDB-id

4ni7; SNAP-derived features in text and JSON formats; DNAproDB

Class

cytokine-DNA

Method

X-ray (2.4 Å)

Summary

Crystal structure of human interleukin 6 in complex with a modified nucleotide aptamer (somamer sl1025)

Reference

Gelinas AD, Davies DR, Edwards TE, Rohloff JC, Carter JD, Zhang C, Gupta S, Ishikawa Y, Hirota M, Nakaishi Y, Jarvis TC, Janjic N (2014): "Crystal structure of interleukin-6 in complex with a modified nucleic Acid ligand." J.Biol.Chem., 289, 8720-8734. doi: 10.1074/jbc.M113.532697.

Abstract

IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Due to its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (Slow Off-rate Modified Aptamers) that bind IL-6 and inhibit its biological activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here we report the co-crystal structure of a high-affinity SOMAmer (Kd=0.20 nM) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd=270 nM). A single substitution from our diverse modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd=7.4 nM). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer:IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets.