Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2

• DOI: 10.1038/ncomms7923
• Publication Date: 2015-04-22T15:33:40Z
• Authors: Dominik Oberthür; John Achenbach; Azat Gabdulkhakov; Klaus Buchner; Christian Maasch; Sven Falke; Dirk Rehders; Sven Klussmann; Christian Betzel
• Keywords: Aptamer

Abstract We report the crystal structure of a 40mer mirror-image RNA oligonucleotide completely built from nucleotides non-natural L -chirality in complex with pro-inflammatory chemokine -CLL2 (monocyte chemoattractant protein-1), natural protein composed regular -amino acids. The -oligonucleotide is an -aptamer (a Spiegelmer) identified to bind -CCL2 high affinity, thereby neutralizing chemokine’s activity. CCL2 plays key role attracting and positioning monocytes; its overexpression several inflammatory diseases makes interesting pharmacological target. PEGylated form -aptamer, NOX-E36 (emapticap pegol), already showed promising efficacy clinical Phase II studies conducted diabetic nephropathy patients. -oligonucleotide· -protein was solved refined 2.05 Å. It unveils -aptamer’s intramolecular contacts permits detailed analysis structure–function relationship. Furthermore, intermolecular drug–target interactions reveals insight into selectivity for certain related chemokines.