4WB2

Crystal structure of the mirror-image L-RNA/L-DNA aptamer NOX-D20 in complex with mouse C5a complement anaphylatoxin

Summary for 4WB2

• Entry DOI: 10.2210/pdb4wb2/pdb
• Descriptor: Complement C5, mixed L-RNA/L-DNA mirror-image aptamer NOX-D20 (40-MER), ACETATE ION, ... (6 entities in total)
• Functional Keywords: protein-rna complex, mirror-image aptamer, g-quadruplex, complement anaphylatoxin, dna-rna hybrid
• Biological source: Mus musculus (House Mouse); More
• Cellular location: Secreted: P06684
• Total number of polymer chains: 5
• Total formula weight: 53699.52

Authors

Yatime, L.,Maasch, C.,Hoehlig, K.,Klussmann, S.,Vater, A.,Andersen, G.R. (deposition date: 2014-09-02, release date: 2015-05-06, Last modification date: 2024-10-23)

Primary citation

Yatime, L.,Maasch, C.,Hoehlig, K.,Klussmann, S.,Andersen, G.R.,Vater, A.
Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer.
Nat Commun, 6:6481-6481, 2015

PubMed Abstract: L-Oligonucleotide aptamers (Spiegelmers) consist of non-natural L-configured nucleotides and are of particular therapeutic interest due to their high resistance to plasma nucleases. The anaphylatoxin C5a, a potent inflammatory mediator generated during complement activation that has been implicated with organ damage, can be efficiently targeted by Spiegelmers. Here, we present the first crystallographic structures of an active Spiegelmer, NOX-D20, bound to its physiological targets, mouse C5a and C5a-desArg. The structures reveal a complex 3D architecture for the L-aptamer that wraps around C5a, including an intramolecular G-quadruplex stabilized by a central Ca(2+) ion. Functional validation of the observed L-aptamer:C5a binding mode through mutational studies also rationalizes the specificity of NOX-D20 for mouse and human C5a against macaque and rat C5a. Finally, our structural model provides the molecular basis for the Spiegelmer affinity improvement through positional L-ribonucleotide to L-deoxyribonucleotide exchanges and for its inhibition of the C5a:C5aR interaction.

PubMed: 25901944
DOI: 10.1038/ncomms7481

Experimental method

X-RAY DIFFRACTION (1.8 Å)