4R8I

High Resolution Structure of a Mirror-Image RNA Oligonucleotide Aptamer in Complex with the Chemokine CCL2

Summary for 4R8I

• Entry DOI: 10.2210/pdb4r8i/pdb
• Descriptor: C-C motif chemokine 2, Mirror-Image RNA Oligonucleotide Aptamer NOXE36, SODIUM ION, ... (6 entities in total)
• Functional Keywords: aptamer spiegelmer l-oligonucleotide, cytokine-rna complex, cytokine/rna
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P13500
• Total number of polymer chains: 2
• Total formula weight: 22046.99

Authors

Oberthuer, D.,Achenbach, J.,Gabdulkhakov, A.,Falke, S.,Buchner, K.,Maasch, C.,Rehders, D.,Klussmann, S.,Betzel, C. (deposition date: 2014-09-02, release date: 2015-04-29, Last modification date: 2024-10-30)

Primary citation

Oberthur, D.,Achenbach, J.,Gabdulkhakov, A.,Buchner, K.,Maasch, C.,Falke, S.,Rehders, D.,Klussmann, S.,Betzel, C.
Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2.
Nat Commun, 6:6923-6923, 2015

PubMed 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.

PubMed: 25901662
DOI: 10.1038/ncomms7923

Experimental method

X-RAY DIFFRACTION (2.05 Å)