View source for 5js2


==Human Argonaute-2 Bound to a Modified siRNA==
<StructureSection load='5js2' size='340' side='right'caption='[[5js2]], [[Resolution|resolution]] 2.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5js2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=5JS2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JS2 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]] 2.954&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6NW:2-O-METHYL-5-O-THIOPHOSPHONOADENOSINE'>6NW</scene>, <scene name='pdbligand=6OO:2-O-METHYL-5-O-THIOPHOSPHONOCYTIDINE'>6OO</scene>, <scene name='pdbligand=6OP:1-[(5E)-5,6-DIDEOXY-2-O-(2-METHOXYETHYL)-6-PHOSPHONO-BETA-D-RIBO-HEX-5-ENOFURANOSYL]-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE'>6OP</scene>, <scene name='pdbligand=F2T:2-DEOXY-2-FLUORO-5-O-THIOPHOSPHONOURIDINE'>F2T</scene>, <scene name='pdbligand=IPH:PHENOL'>IPH</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=UFT:2-DEOXY-2-FLUOROURIDINE+5-(DIHYDROGEN+PHOSPHATE)'>UFT</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=5js2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5js2 OCA], [https://pdbe.org/5js2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5js2 RCSB], [https://www.ebi.ac.uk/pdbsum/5js2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5js2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AGO2_HUMAN AGO2_HUMAN] Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include EIF2C2/AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by EIF2C2/AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.<ref>PMID:15105377</ref> <ref>PMID:15260970</ref> <ref>PMID:15337849</ref> <ref>PMID:15284456</ref> <ref>PMID:16271387</ref> <ref>PMID:16289642</ref> <ref>PMID:16142218</ref> <ref>PMID:16357216</ref> <ref>PMID:15800637</ref> <ref>PMID:16081698</ref> <ref>PMID:16936728</ref> <ref>PMID:16756390</ref> <ref>PMID:17382880</ref> <ref>PMID:17524464</ref> <ref>PMID:17932509</ref> <ref>PMID:17531811</ref> <ref>PMID:17507929</ref> <ref>PMID:18048652</ref> <ref>PMID:18771919</ref> <ref>PMID:18690212</ref> <ref>PMID:18178619</ref> <ref>PMID:19167051</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Incorporation of chemical modifications into small interfering RNAs (siRNAs) increases their metabolic stability and improves their tissue distribution. However, how these modifications impact interactions with Argonaute-2 (Ago2), the molecular target of siRNAs, is not known. Herein we present the crystal structure of human Ago2 bound to a metabolically stable siRNA containing extensive backbone modifications. Comparison to the structure of an equivalent unmodified-siRNA complex indicates that the structure of Ago2 is relatively unaffected by chemical modifications in the bound siRNA. In contrast, the modified siRNA appears to be much more plastic and shifts, relative to the unmodified siRNA, to optimize contacts with Ago2. Structure-activity analysis reveals that even major conformational perturbations in the 3' half of the siRNA seed region have a relatively modest effect on knockdown potency. These findings provide an explanation for a variety of modification patterns tolerated in siRNAs and a structural basis for advancing therapeutic siRNA design.

Structural Analysis of Human Argonaute-2 Bound to a Modified siRNA Guide.,Schirle NT, Kinberger GA, Murray HF, Lima WF, Prakash TP, MacRae IJ J Am Chem Soc. 2016 Jul 20;138(28):8694-7. doi: 10.1021/jacs.6b04454. Epub 2016, Jul 12. PMID:27380263<ref>PMID:27380263</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5js2" style="background-color:#fffaf0;"></div>

==See Also==
*[[Argonaute 3D structures|Argonaute 3D structures]]
*[[Eukaryotic initiation factor 3D structures|Eukaryotic initiation factor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: MacRae IJ]]
[[Category: Schirle NT]]