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PDBsum entry 4wb3
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DNA-RNA hybrid
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PDB id
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4wb3
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PDB id:
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| Name: |
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DNA-RNA hybrid
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Title:
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Crystal structure of the mirror-image l-RNA/l-DNA aptamer nox-d20 in complex with mouse c5a-desarg complement anaphylatoxin
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Structure:
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Complement c5. Chain: a, b, c. Synonym: hemolytic complement. Engineered: yes. Mixed l-RNA/l-DNA aptamer nox-d20 (40-mer). Chain: d, e. Engineered: yes
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Source:
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Mus musculus. Mouse. Organism_taxid: 10090. Gene: c5, hc. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630
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Resolution:
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2.00Å
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R-factor:
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0.165
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R-free:
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0.199
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Authors:
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L.Yatime,C.Maasch,K.Hoehlig,S.Klussmann,A.Vater,G.R.Andersen
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Key ref:
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L.Yatime
et al.
(2015).
Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer.
Nat Commun,
6,
6481.
PubMed id:
DOI:
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Date:
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02-Sep-14
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Release date:
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06-May-15
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PROCHECK
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Headers
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References
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P06684
(CO5_MOUSE) -
Complement C5 from Mus musculus
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Seq:
Struc:
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1680 a.a.
68 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Nat Commun
6:6481
(2015)
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PubMed id:
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Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer.
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L.Yatime,
C.Maasch,
K.Hoehlig,
S.Klussmann,
G.R.Andersen,
A.Vater.
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ABSTRACT
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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.
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Links
