4wb2: Difference between revisions
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The | ==Crystal structure of the mirror-image L-RNA/L-DNA aptamer NOX-D20 in complex with mouse C5a complement anaphylatoxin== | ||
<StructureSection load='4wb2' size='340' side='right'caption='[[4wb2]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4wb2]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WB2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WB2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0A:L-ADENOSINE-5-MONOPHOSPHATE'>0A</scene>, <scene name='pdbligand=0C:L-CYTIDINE-5-MONOPHOSPHATE'>0C</scene>, <scene name='pdbligand=0DA:2-DEOXY-L-RIBO-FURANOSYL+ADENOSINE-5-MONOPHOSPHATE'>0DA</scene>, <scene name='pdbligand=0DC:2-DEOXY-L-RIBO-FURANOSYL+CYTOSINE-5-MONOPHOSPHATE'>0DC</scene>, <scene name='pdbligand=0DG:2-DEOXY-L-RIBO-FURANOSYL+GUANINE-5-MONOPHOSPHATE'>0DG</scene>, <scene name='pdbligand=0G:L-GUANOSINE-5-MONOPHOSPHATE'>0G</scene>, <scene name='pdbligand=0U:L-URIDINE-5-MONOPHOSPHATE'>0U</scene>, <scene name='pdbligand=3KA:1-(2-DEOXY-5-O-PHOSPHONO-BETA-L-ERYTHRO-PENTOFURANOSYL)PYRIMIDINE-2,4(1H,3H)-DIONE'>3KA</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4wb2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wb2 OCA], [https://pdbe.org/4wb2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wb2 RCSB], [https://www.ebi.ac.uk/pdbsum/4wb2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wb2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CO5_MOUSE CO5_MOUSE] Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled. Derived from proteolytic degradation of complement C5, C5 anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. C5a also stimulates the locomotion of polymorphonuclear leukocytes (chemokinesis) and direct their migration toward sites of inflammation (chemotaxis). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | |||
Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer.,Yatime L, Maasch C, Hoehlig K, Klussmann S, Andersen GR, Vater A Nat Commun. 2015 Apr 22;6:6481. doi: 10.1038/ncomms7481. PMID:25901944<ref>PMID:25901944</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4wb2" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Complement C5 3D structures|Complement C5 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mus musculus]] | |||
[[Category: Synthetic construct]] | |||
[[Category: Andersen GR]] | |||
[[Category: Hoehlig K]] | |||
[[Category: Klussmann S]] | |||
[[Category: Maasch C]] | |||
[[Category: Vater A]] | |||
[[Category: Yatime L]] | |||