View source for 6cxz


==RNA octamer containing 2'-F, 4'-Calpha-Me U.==
<StructureSection load='6cxz' size='340' side='right'caption='[[6cxz]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6cxz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CXZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CXZ 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]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=NCO:COBALT+HEXAMMINE(III)'>NCO</scene>, <scene name='pdbligand=U4M:[(2~{R},3~{R},4~{R},5~{R})-5-[2,4-bis(oxidanylidene)pyrimidin-1-yl]-4-fluoranyl-2-methyl-3-oxidanyl-oxolan-2-yl]methyl+dihydrogen+phosphate'>U4M</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=6cxz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cxz OCA], [https://pdbe.org/6cxz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cxz RCSB], [https://www.ebi.ac.uk/pdbsum/6cxz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cxz ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Chemical modification is a prerequisite of oligonucleotide therapeutics for improved metabolic stability, uptake and activity, irrespective of their mode of action, i.e. antisense, RNAi or aptamer. Phosphate moiety and ribose C2'/O2' atoms are the most common sites for modification. Compared to 2'-O-substituents, ribose 4'-C-substituents lie in proximity of both the 3'- and 5'-adjacent phosphates. To investigate potentially beneficial effects on nuclease resistance we combined 2'-F and 2'-OMe with 4'-Calpha- and 4'-Cbeta-OMe, and 2'-F with 4'-Calpha-methyl modification. The alpha- and beta-epimers of 4'-C-OMe-uridine and the alpha-epimer of 4'-C-Me-uridine monomers were synthesized and incorporated into siRNAs. The 4'alpha-epimers affect thermal stability only minimally and show increased nuclease stability irrespective of the 2'-substituent (H, F, OMe). The 4'beta-epimers are strongly destabilizing, but afford complete resistance against an exonuclease with the phosphate or phosphorothioate backbones. Crystal structures of RNA octamers containing 2'-F,4'-Calpha-OMe-U, 2'-F,4'-Cbeta-OMe-U, 2'-OMe,4'-Calpha-OMe-U, 2'-OMe,4'-Cbeta-OMe-U or 2'-F,4'-Calpha-Me-U help rationalize these observations and point to steric and electrostatic origins of the unprecedented nuclease resistance seen with the chain-inverted 4'beta-U epimer. We used structural models of human Argonaute 2 in complex with guide siRNA featuring 2'-F,4'-Calpha-OMe-U or 2'-F,4'-Cbeta-OMe-U at various sites in the seed region to interpret in vitro activities of siRNAs with the corresponding 2'-/4'-C-modifications.

Structural basis for the synergy of 4'- and 2'-modifications on siRNA nuclease resistance, thermal stability and RNAi activity.,Harp JM, Guenther DC, Bisbe A, Perkins L, Matsuda S, Bommineni GR, Zlatev I, Foster DJ, Taneja N, Charisse K, Maier MA, Rajeev KG, Manoharan M, Egli M Nucleic Acids Res. 2018 Aug 11. pii: 5070490. doi: 10.1093/nar/gky703. PMID:30107495<ref>PMID:30107495</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6cxz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Egli M]]
[[Category: Harp JM]]