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Nat Commun. 2015 Apr 22;6:6923. doi: 10.1038/ncomms7923.

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

Author information

1
1] Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany [2] Center for Free-Electron Laser Science, Deutsches Elektronen Synchrotron-DESY, Notkestrasse 85, 22607 Hamburg, Germany.
2
NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
3
Institute of Protein Research, RAS, Pushchino, Moscow Region 142290, Russian Federation.
4
Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY Building 22a, Notkestrasse 85, 22607 Hamburg, Germany.

Abstract

We report the crystal structure of a 40 mer 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[Symbol: see text]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.

PMID:
25901662
PMCID:
PMC4423205
DOI:
10.1038/ncomms7923
[Indexed for MEDLINE]
Free PMC Article

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