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

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  • Dominik Oberthür

    (Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg
    Center for Free-Electron Laser Science, Deutsches Elektronen Synchrotron-DESY)

  • John Achenbach

    (NOXXON Pharma AG)

  • Azat Gabdulkhakov

    (Institute of Protein Research, RAS, Pushchino)

  • Klaus Buchner

    (NOXXON Pharma AG)

  • Christian Maasch

    (NOXXON Pharma AG)

  • Sven Falke

    (Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg)

  • Dirk Rehders

    (Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg)

  • Sven Klussmann

    (NOXXON Pharma AG)

  • Christian Betzel

    (Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg)

Abstract

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

Suggested Citation

  • Dominik Oberthür & John Achenbach & Azat Gabdulkhakov & Klaus Buchner & Christian Maasch & Sven Falke & Dirk Rehders & Sven Klussmann & Christian Betzel, 2015. "Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7923
    DOI: 10.1038/ncomms7923
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