7c6b: Difference between revisions

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'''Unreleased structure'''


The entry 7c6b is ON HOLD
==Crystal structure of Ago2 MID domain in complex with 6-(3-(2-carboxyethyl)phenyl)purine riboside monophosphate==
<StructureSection load='7c6b' size='340' side='right'caption='[[7c6b]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7c6b]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C6B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7C6B 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K2R:3-[3-[9-[(2R,3R,4S,5R)-3,4-bis(oxidanyl)-5-(phosphonooxymethyl)oxolan-2-yl]purin-6-yl]phenyl]propanoic+acid'>K2R</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7c6b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c6b OCA], [https://pdbe.org/7c6b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7c6b RCSB], [https://www.ebi.ac.uk/pdbsum/7c6b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7c6b 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 ==
Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been employed to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5' nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analogue, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analogue at the 5'-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.


Authors:  
siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand.,Shinohara F, Oashi T, Harumoto T, Nishikawa T, Takayama Y, Miyagi H, Takahashi Y, Nakajima T, Sawada T, Koda Y, Makino A, Sato A, Hamaguch K, Suzuki M, Yamamoto J, Tomari Y, Saito JI RNA. 2020 Nov 11. pii: rna.073783.119. doi: 10.1261/rna.073783.119. PMID:33177188<ref>PMID:33177188</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 7c6b" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Argonaute 3D structures|Argonaute 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Miyagi H]]
[[Category: Saito J]]
[[Category: Shinohara F]]
[[Category: Suzuki M]]
[[Category: Takahashi Y]]

Latest revision as of 18:57, 29 November 2023

Crystal structure of Ago2 MID domain in complex with 6-(3-(2-carboxyethyl)phenyl)purine riboside monophosphateCrystal structure of Ago2 MID domain in complex with 6-(3-(2-carboxyethyl)phenyl)purine riboside monophosphate

Structural highlights

7c6b is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]

Publication Abstract from PubMed

Small interfering RNAs (siRNAs) can be utilized not only as functional biological research tools but also as therapeutic agents. For the clinical use of siRNA as drugs, various chemical modifications have been employed to improve the activity of siRNA drugs, and further chemical modifications are expected to improve the utility of siRNA therapeutics. As the 5' nucleobase of the guide strand affects the interaction between an siRNA and AGO2 and target cleavage activity, structural optimization of this specific position may be a useful strategy for improving siRNA activity. Here, using the in silico model of the complex between human AGO2 MID domain and nucleoside monophosphates, we screened and synthesized an original adenine-derived analogue, 6-(3-(2-carboxyethyl)phenyl)purine (6-mCEPh-purine), that fits better than the natural nucleotide bases into the MID domain of AGO2. Introduction of the 6-mCEPh-purine analogue at the 5'-end of the siRNA guide strand significantly enhanced target knockdown activity in both cultured cell lines and in vivo animal models. Our findings can help expand strategies for rationally optimizing siRNA activity via chemical modifications of nucleotide bases.

siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand.,Shinohara F, Oashi T, Harumoto T, Nishikawa T, Takayama Y, Miyagi H, Takahashi Y, Nakajima T, Sawada T, Koda Y, Makino A, Sato A, Hamaguch K, Suzuki M, Yamamoto J, Tomari Y, Saito JI RNA. 2020 Nov 11. pii: rna.073783.119. doi: 10.1261/rna.073783.119. PMID:33177188[23]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Martinez J, Tuschl T. RISC is a 5' phosphomonoester-producing RNA endonuclease. Genes Dev. 2004 May 1;18(9):975-80. Epub 2004 Apr 22. PMID:15105377 doi:http://dx.doi.org/10.1101/gad.1187904
  2. ↑ Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell. 2004 Jul 23;15(2):185-97. PMID:15260970 doi:http://dx.doi.org/10.1016/j.molcel.2004.07.007
  3. ↑ Pillai RS, Artus CG, Filipowicz W. Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis. RNA. 2004 Oct;10(10):1518-25. Epub 2004 Aug 30. PMID:15337849 doi:http://dx.doi.org/10.1261/rna.7131604
  4. ↑ Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, Song JJ, Hammond SM, Joshua-Tor L, Hannon GJ. Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004 Sep 3;305(5689):1437-41. Epub 2004 Jul 29. PMID:15284456 doi:http://dx.doi.org/10.1126/science.1102513
  5. ↑ Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005 Nov 18;123(4):631-40. Epub 2005 Nov 3. PMID:16271387 doi:10.1016/j.cell.2005.10.022
  6. ↑ Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Luhrmann R, Tuschl T. Identification of novel argonaute-associated proteins. Curr Biol. 2005 Dec 6;15(23):2149-55. Epub 2005 Nov 10. PMID:16289642 doi:10.1016/j.cub.2005.10.048
  7. ↑ Haase AD, Jaskiewicz L, Zhang H, Laine S, Sack R, Gatignol A, Filipowicz W. TRBP, a regulator of cellular PKR and HIV-1 virus expression, interacts with Dicer and functions in RNA silencing. EMBO Rep. 2005 Oct;6(10):961-7. PMID:16142218 doi:10.1038/sj.embor.7400509
  8. ↑ Maniataki E, Mourelatos Z. A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev. 2005 Dec 15;19(24):2979-90. PMID:16357216 doi:10.1101/gad.1384005
  9. ↑ Rivas FV, Tolia NH, Song JJ, Aragon JP, Liu J, Hannon GJ, Joshua-Tor L. Purified Argonaute2 and an siRNA form recombinant human RISC. Nat Struct Mol Biol. 2005 Apr;12(4):340-9. Epub 2005 Mar 30. PMID:15800637 doi:10.1038/nsmb918
  10. ↑ Pillai RS, Bhattacharyya SN, Artus CG, Zoller T, Cougot N, Basyuk E, Bertrand E, Filipowicz W. Inhibition of translational initiation by Let-7 MicroRNA in human cells. Science. 2005 Sep 2;309(5740):1573-6. Epub 2005 Aug 4. PMID:16081698 doi:http://dx.doi.org/10.1126/science.1115079
  11. ↑ Janowski BA, Huffman KE, Schwartz JC, Ram R, Nordsell R, Shames DS, Minna JD, Corey DR. Involvement of AGO1 and AGO2 in mammalian transcriptional silencing. Nat Struct Mol Biol. 2006 Sep;13(9):787-92. Epub 2006 Aug 27. PMID:16936728 doi:nsmb1140
  12. ↑ Chu CY, Rana TM. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biol. 2006 Jul;4(7):e210. PMID:16756390 doi:http://dx.doi.org/06-PLBI-RA-0036R3
  13. ↑ Vasudevan S, Steitz JA. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell. 2007 Mar 23;128(6):1105-18. PMID:17382880 doi:http://dx.doi.org/10.1016/j.cell.2007.01.038
  14. ↑ Kiriakidou M, Tan GS, Lamprinaki S, De Planell-Saguer M, Nelson PT, Mourelatos Z. An mRNA m7G cap binding-like motif within human Ago2 represses translation. Cell. 2007 Jun 15;129(6):1141-51. Epub 2007 May 24. PMID:17524464 doi:http://dx.doi.org/10.1016/j.cell.2007.05.016
  15. ↑ Hock J, Weinmann L, Ender C, Rudel S, Kremmer E, Raabe M, Urlaub H, Meister G. Proteomic and functional analysis of Argonaute-containing mRNA-protein complexes in human cells. EMBO Rep. 2007 Nov;8(11):1052-60. Epub 2007 Oct 12. PMID:17932509 doi:http://dx.doi.org/7401088
  16. ↑ Robb GB, Rana TM. RNA helicase A interacts with RISC in human cells and functions in RISC loading. Mol Cell. 2007 May 25;26(4):523-37. PMID:17531811 doi:http://dx.doi.org/10.1016/j.molcel.2007.04.016
  17. ↑ Chendrimada TP, Finn KJ, Ji X, Baillat D, Gregory RI, Liebhaber SA, Pasquinelli AE, Shiekhattar R. MicroRNA silencing through RISC recruitment of eIF6. Nature. 2007 Jun 14;447(7146):823-8. Epub 2007 May 16. PMID:17507929 doi:http://dx.doi.org/10.1038/nature05841
  18. ↑ Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007 Dec 21;318(5858):1931-4. Epub 2007 Nov 29. PMID:18048652 doi:http://dx.doi.org/10.1126/science.1149460
  19. ↑ Wu L, Fan J, Belasco JG. Importance of translation and nonnucleolytic ago proteins for on-target RNA interference. Curr Biol. 2008 Sep 9;18(17):1327-32. doi: 10.1016/j.cub.2008.07.072. PMID:18771919 doi:10.1016/j.cub.2008.07.072
  20. ↑ Qi HH, Ongusaha PP, Myllyharju J, Cheng D, Pakkanen O, Shi Y, Lee SW, Peng J, Shi Y. Prolyl 4-hydroxylation regulates Argonaute 2 stability. Nature. 2008 Sep 18;455(7211):421-4. doi: 10.1038/nature07186. Epub 2008 Aug 6. PMID:18690212 doi:http://dx.doi.org/10.1038/nature07186
  21. ↑ MacRae IJ, Ma E, Zhou M, Robinson CV, Doudna JA. In vitro reconstitution of the human RISC-loading complex. Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):512-7. doi: 10.1073/pnas.0710869105., Epub 2008 Jan 4. PMID:18178619 doi:10.1073/pnas.0710869105
  22. ↑ Weinmann L, Hock J, Ivacevic T, Ohrt T, Mutze J, Schwille P, Kremmer E, Benes V, Urlaub H, Meister G. Importin 8 is a gene silencing factor that targets argonaute proteins to distinct mRNAs. Cell. 2009 Feb 6;136(3):496-507. doi: 10.1016/j.cell.2008.12.023. Epub 2009 Jan, 22. PMID:19167051 doi:http://dx.doi.org/10.1016/j.cell.2008.12.023
  23. ↑ Shinohara F, Oashi T, Harumoto T, Nishikawa T, Takayama Y, Miyagi H, Takahashi Y, Nakajima T, Sawada T, Koda Y, Makino A, Sato A, Hamaguchi K, Suzuki M, Yamamoto J, Tomari Y, Saito JI. siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand. RNA. 2021 Feb;27(2):163-173. PMID:33177188 doi:10.1261/rna.073783.119

7c6b, resolution 1.70Å

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