Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand

Abstract

Background: Traditional aptamers favor polar interactions with protein binding partners.Results: The IL-6·SOMAmer structure reveals an interface rich in hydrophobic interactions that overlap the binding sites of IL-6 receptors.Conclusion: Hydrophobic modifications on DNA scaffolds generate diverse and novel structural motifs.Significance: Synthetic SOMAmers are potent, specific, and chemically versatile ligands with distinct binding properties compared with conventional aptamers.

Customised nucleic acid libraries for enhanced aptamer selection and performance

“…In comparison to conventional aptamers, the amount of polar contacts of SOMAmers to target molecules has been found to be decreased [20] and instead architectures with hydrophobic networks within a SOMAmer are formed, thus enabling the adoption of binding modalities that mimic those found in proteins. In these, the artificial nucleotides largely contribute to the interaction with the respective target protein [17,20]. The amide linker has been observed to contribute to the folding of SOMAmers and to the interaction with the target protein, that is by hydrogen-bonding [18,20,21 ].…”

“…Artificial nucleotides also enable the formation of novel three-dimensional structures of aptamers [16,20]. In comparison to conventional aptamers, the amount of polar contacts of SOMAmers to target molecules has been found to be decreased [20] and instead architectures with hydrophobic networks within a SOMAmer are formed, thus enabling the adoption of binding modalities that mimic those found in proteins.…”

“…In these, the artificial nucleotides largely contribute to the interaction with the respective target protein [17,20]. The amide linker has been observed to contribute to the folding of SOMAmers and to the interaction with the target protein, that is by hydrogen-bonding [18,20,21 ].…”

Towards applications of synthetic genetic polymers in diagnosis and therapy

“…a growth factor (PDGF) [21] and a proinflammatory cytokine (IL-6). In the latter case, the modified aptamers achieve high affinity through extensive hydrophobic contacts with their target, visible in a crystal structure of the complex [23 ], and can mediate promising biological effects, at least in vitro (inhibition of signalling by blocking IL-6 binding to its receptor in a cell culture proliferation assay) [24 ]. Imaizumi et al show that a similar base modification may be used to select aptamers against a small molecule (Camptotecin, a quinolone alkaloid) [25].…”

An affibody-adalimumab hybrid blocks combined IL-6 and TNF-triggered serum amyloid A secretion in vivo

“…2,27 Interestingly, a recently described, and also in vitro selected, nucleic acid aptamer to IL-6 has been shown to preferentially bind to the gp130 interacting surface characterized by this more rigid nature, although the aptamer structure also extends into the IL-6Ra/IL-6 interaction interface enough to affect that interaction. 28,29 However, from a library of antibody-like binders called "minibodies," binders to IL-6 have been selected that interfere with the IL-6Ra/IL-6 interaction, suggesting that the regions of IL-6 showing the increased mobility may indeed be addressed by in vitro selection. 30,31 The IL-6 signal generating complex involves the formation of a hexameric structure that can be obstructed also by other means.…”