4NI7

Crystal structure of human interleukin 6 in complex with a modified nucleotide aptamer (SOMAMER SL1025)

Summary for 4NI7

• Entry DOI: 10.2210/pdb4ni7/pdb
• Descriptor: Interleukin-6, SOMAmer SL1025, SODIUM ION, ... (4 entities in total)
• Functional Keywords: interleukin-6, cytokine-dna complex, cytokine/dna
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P05231
• Total number of polymer chains: 2
• Total formula weight: 32586.00

Authors

Davies, D.,Edwards, T.,Gelinas, A.,Jarvis, T.,Clifton, M.C. (deposition date: 2013-11-05, release date: 2014-01-22, Last modification date: 2024-11-20)

Primary citation

Gelinas, A.D.,Davies, D.R.,Edwards, T.E.,Rohloff, J.C.,Carter, J.D.,Zhang, C.,Gupta, S.,Ishikawa, Y.,Hirota, M.,Nakaishi, Y.,Jarvis, T.C.,Janjic, N.
Crystal structure of interleukin-6 in complex with a modified nucleic Acid ligand.
J.Biol.Chem., 289:8720-8734, 2014

PubMed Abstract: IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of 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 (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic 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 diversely 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.

PubMed: 24415767
DOI: 10.1074/jbc.M113.532697

Experimental method

X-RAY DIFFRACTION (2.4 Å)