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PDBsum entry 1z26

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protein ligands links
Gene regulation PDB id
1z26
Jmol
Contents
Protein chain
716 a.a. *
Ligands
WO4-WO4
WO4
Waters ×140
* Residue conservation analysis
PDB id:
1z26
Name: Gene regulation
Title: Structure of pyrococcus furiosus argonaute with bound tungstate
Structure: Argonaute. Chain: a. Engineered: yes. Mutation: yes
Source: Pyrococcus furiosus. Organism_taxid: 2261. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.50Å     R-factor:   0.224     R-free:   0.282
Authors: F.V.Rivas,N.H.Tolia,J.J.Song,J.P.Aragon,J.Liu,G.J.Hannon, L.Joshua-Tor
Key ref:
F.V.Rivas et al. (2005). Purified Argonaute2 and an siRNA form recombinant human RISC. Nat Struct Mol Biol, 12, 340-349. PubMed id: 15800637 DOI: 10.1038/nsmb918
Date:
07-Mar-05     Release date:   05-Apr-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q8U3D2  (Q8U3D2_PYRFU) -  Uncharacterized protein
Seq:
Struc:
 
Seq:
Struc:
770 a.a.
716 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biochemical function     nucleic acid binding     2 terms  

 

 
DOI no: 10.1038/nsmb918 Nat Struct Mol Biol 12:340-349 (2005)
PubMed id: 15800637  
 
 
Purified Argonaute2 and an siRNA form recombinant human RISC.
F.V.Rivas, N.H.Tolia, J.J.Song, J.P.Aragon, J.Liu, G.J.Hannon, L.Joshua-Tor.
 
  ABSTRACT  
 
Genetic, biochemical and structural studies have implicated Argonaute proteins as the catalytic core of the RNAi effector complex, RISC. Here we show that recombinant, human Argonaute2 can combine with a small interfering RNA (siRNA) to form minimal RISC that accurately cleaves substrate RNAs. Recombinant RISC shows many of the properties of RISC purified from human or Drosophila melanogaster cells but also has surprising features. It shows no stimulation by ATP, suggesting that factors promoting product release are missing from the recombinant enzyme. The active site is made up of a unique Asp-Asp-His (DDH) motif. In the RISC reconstitution system, the siRNA 5' phosphate is important for the stability and the fidelity of the complex but is not essential for the creation of an active enzyme. These studies demonstrate that Argonaute proteins catalyze mRNA cleavage within RISC and provide a source of recombinant enzyme for detailed biochemical studies of the RNAi effector complex.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Cleavage by recombinant RISC is accurate. (a) siRNAs either bearing or lacking 5' phosphates (as indicated) were used to reconstitute RISC with recombinant hAgo2. Sequences were removed from either the 5' or 3' end to create shorter siRNAs of the indicated lengths. Positions of the substrate and the 5' product are shown. Products were analyzed on 20% (w/v) PAGE gels. b, base. (b) Synthetic substrates used in c are shown along with the siRNA used to reconstitute RISC. The predicted cleavage position is indicated by the arrow. Red nucleotides denote the position of the phosphorothioate as being 5' to the highlighted position. Asterisk, observed position of cleavage of S2 in the absence of the 5' phosphate on the siRNA. (c) Phosphorylated or nonphosphorylated siRNA of the sequence in b was used to program recombinant Ago2. This was reacted with the indicated substrate in the presence of Mg2+ or Mn2+ or in the absence of divalent metal. Positions of the substrate and 5' product are indicated. Asterisk denotes inaccurate cleavage of S2 in the absence of the siRNA 5' phosphate. Gels shown are representative of at least three independent repeats. b, base. WT, wild type.
Figure 4.
Figure 4. Position of the 5' end of the siRNA in RISC. (a) siRNAs derivatized with iodouridine at selected positions (red) were mixed with 293 cell extracts containing epitope tagged human Ago1 or Ago2. After UV irradiation, crosslinked species were recovered by immunoprecipitation and resolved by gel electrophoresis. (b) Ribbon representation of PfAgo showing the N-terminal domain (blue), the stalk (light blue), the PAZ domain (red), the middle domain (green), the PIWI domain (purple), and the interdomain connector (yellow). The molecule is shown from one end of the groove toward the active site (marked by a red asterisk). The active site aspartates are in stick representation. Disordered loops are dotted lines. The difference Fourier electron density map contoured at 5 (aquamarine) shows the tungstate-binding sites. Site 1 is a double peak shown in the front at one end of the binding site groove leading to the active site. Site 2 is nestled between the stalk and the interdomain connector and less accessible to an oligonucleotide. (c) F[o] - F[c] electron density map (left) contoured at 5 around tungstate-binding site 1. The double peak indicates two close tungstate positions (see text). A tungstate ion modeled into the density (right) with tungsten in orange and oxygen in red (only one is shown for clarity). Three lysines, two of which reside on the PIWI box, form a positively charged pocket suitable for phosphate binding. (d) An A-form RNA decamer duplex was placed in the main groove of PfAgo with the 5' end of the siRNA (purple) near the tungstate-binding site 1 (aquamarine sphere) (see text and Methods). The scissile phosphate on the target mRNA (light blue) is at a position opposite to the phosphate between nucleotides 10 and 11 of the siRNA. In this model, this phosphate falls near the active site aspartates (red). The view on the left is identical to the view in; the view on the right is rotated 60 around the horizontal axis.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2005, 12, 340-349) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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PDB codes: 3pja 3qb5
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20639883 T.Miyoshi, A.Takeuchi, H.Siomi, and M.C.Siomi (2010).
A direct role for Hsp90 in pre-RISC formation in Drosophila.
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20211138 T.Noto, H.M.Kurth, K.Kataoka, L.Aronica, L.V.DeSouza, K.W.Siu, R.E.Pearlman, M.A.Gorovsky, and K.Mochizuki (2010).
The Tetrahymena argonaute-binding protein Giw1p directs a mature argonaute-siRNA complex to the nucleus.
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20386665 V.Salvatore, N.Potenza, U.Papa, V.Nobile, and A.Russo (2010).
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20427423 X.Abad, N.Razquin, A.Abad, and P.Fortes (2010).
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20454920 X.Zhou, H.Guo, K.Chen, H.Cheng, and R.Zhou (2010).
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19946268 B.Wang, S.Li, H.H.Qi, D.Chowdhury, Y.Shi, and C.D.Novina (2009).
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19470757 D.Baillat, and R.Shiekhattar (2009).
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Hsp90 regulates the function of argonaute 2 and its recruitment to stress granules and P-bodies.
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19508234 K.M.Felice, D.W.Salzman, J.Shubert-Coleman, K.P.Jensen, and H.M.Furneaux (2009).
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19451544 K.Miyoshi, T.N.Okada, H.Siomi, and M.C.Siomi (2009).
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19223321 M.I.Trombly, H.Su, and X.Wang (2009).
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Structural and functional modules in RNA interference.
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19668211 P.Landry, I.Plante, D.L.Ouellet, M.P.Perron, G.Rousseau, and P.Provost (2009).
Existence of a microRNA pathway in anucleate platelets.
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19175700 P.W.Lau, and I.J.Macrae (2009).
The molecular machines that mediate microRNA maturation.
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Origins and Mechanisms of miRNAs and siRNAs.
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19779550 S.A.Stanhope, S.Sengupta, J.den Boon, P.Ahlquist, and M.A.Newton (2009).
Statistical use of argonaute expression and RISC assembly in microRNA target identification.
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19767612 T.A.Vickers, W.F.Lima, H.Wu, J.G.Nichols, P.S.Linsley, and S.T.Crooke (2009).
Off-target and a portion of target-specific siRNA mediated mRNA degradation is Ago2 'Slicer' independent and can be mediated by Ago1.
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19684602 T.Kawamata, H.Seitz, and Y.Tomari (2009).
Structural determinants of miRNAs for RISC loading and slicer-independent unwinding.
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PIWI, piRNAs, and germline stem cells: what's the link?
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19524057 V.Alvarado, and H.B.Scholthof (2009).
Plant responses against invasive nucleic acids: RNA silencing and its suppression by plant viral pathogens.
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19625255 W.F.Lima, H.Wu, J.G.Nichols, H.Sun, H.M.Murray, and S.T.Crooke (2009).
Binding and cleavage specificities of human Argonaute2.
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19812667 Y.Wang, S.Juranek, H.Li, G.Sheng, G.S.Wardle, T.Tuschl, and D.J.Patel (2009).
Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes.
  Nature, 461, 754-761.
PDB codes: 3hjf 3hk2 3hm9 3ho1 3hvr 3hxm
18692607 A.van den Berg, J.Mols, and J.Han (2008).
RISC-target interaction: cleavage and translational suppression.
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19032786 D.Zhang, H.Xiong, J.Shan, X.Xia, and V.L.Trudeau (2008).
Functional insight into Maelstrom in the germline piRNA pathway: a unique domain homologous to the DnaQ-H 3'-5' exonuclease, its lineage-specific expansion/loss and evolutionarily active site switch.
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18073770 G.Hutvagner, and M.J.Simard (2008).
Argonaute proteins: key players in RNA silencing.
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18367718 G.Jannot, M.E.Boisvert, I.H.Banville, and M.J.Simard (2008).
Two molecular features contribute to the Argonaute specificity for the microRNA and RNAi pathways in C. elegans.
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Behind the scenes of a small RNA gene-silencing pathway.
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Cloning, expression, purification and preliminary crystallographic analysis of the RNase HI domain of the Mycobacterium tuberculosis protein Rv2228c as a maltose-binding protein fusion.
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18690212 H.H.Qi, P.P.Ongusaha, J.Myllyharju, D.Cheng, O.Pakkanen, Y.Shi, S.W.Lee, J.Peng, and Y.Shi (2008).
Prolyl 4-hydroxylation regulates Argonaute 2 stability.
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18508405 H.Vaucheret (2008).
Plant ARGONAUTES.
  Trends Plant Sci, 13, 350-358.  
18493041 J.A.Casas-Mollano, J.Rohr, E.J.Kim, E.Balassa, K.van Dijk, and H.Cerutti (2008).
Diversification of the core RNA interference machinery in Chlamydomonas reinhardtii and the role of DCL1 in transposon silencing.
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18304383 J.Höck, and G.Meister (2008).
The Argonaute protein family.
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RNA silencing and HIV: a hypothesis for the etiology of the severe combined immunodeficiency induced by the virus.
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Genome-wide identification, organization and phylogenetic analysis of Dicer-like, Argonaute and RNA-dependent RNA Polymerase gene families and their expression analysis during reproductive development and stress in rice.
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18603593 M.Niemann, M.Brecht, E.Schlüter, K.Weitzel, M.Zacharias, and H.U.Göringer (2008).
TbMP42 is a structure-sensitive ribonuclease that likely follows a metal ion catalysis mechanism.
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17981733 M.P.Perron, and P.Provost (2008).
Protein interactions and complexes in human microRNA biogenesis and function.
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18094121 P.Y.Chen, L.Weinmann, D.Gaidatzis, Y.Pei, M.Zavolan, T.Tuschl, and G.Meister (2008).
Strand-specific 5'-O-methylation of siRNA duplexes controls guide strand selection and targeting specificity.
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18342361 S.Mi, T.Cai, Y.Hu, Y.Chen, E.Hodges, F.Ni, L.Wu, S.Li, H.Zhou, C.Long, S.Chen, G.J.Hannon, and Y.Qi (2008).
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18342362 T.A.Montgomery, M.D.Howell, J.T.Cuperus, D.Li, J.E.Hansen, A.L.Alexander, E.J.Chapman, N.Fahlgren, E.Allen, and J.C.Carrington (2008).
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18065653 T.M.Hammond, J.W.Bok, M.D.Andrewski, Y.Reyes-Domínguez, C.Scazzocchio, and N.P.Keller (2008).
RNA Silencing Gene Truncation in the Filamentous Fungus Aspergillus nidulans.
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18842624 T.Ohrt, J.Mütze, W.Staroske, L.Weinmann, J.Höck, K.Crell, G.Meister, and P.Schwille (2008).
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Structure of the guide-strand-containing argonaute silencing complex.
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PDB codes: 3dlb 3dlh
18483081 Z.J.Lu, and D.H.Mathews (2008).
Fundamental differences in the equilibrium considerations for siRNA and antisense oligodeoxynucleotide design.
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P68 RNA helicase unwinds the human let-7 microRNA precursor duplex and is required for let-7-directed silencing of gene expression.
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Specialization and evolution of endogenous small RNA pathways.
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Structure of the C-terminal half of UvrC reveals an RNase H endonuclease domain with an Argonaute-like catalytic triad.
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PDB codes: 2nrr 2nrt 2nrv 2nrw 2nrx 2nrz
17531811 G.B.Robb, and T.M.Rana (2007).
RNA helicase A interacts with RISC in human cells and functions in RISC loading.
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In vitro binding of single-stranded RNA by human Dicer.
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Distinct populations of primary and secondary effectors during RNAi in C. elegans.
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Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by dicer-1.
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17123955 K.Kim, Y.S.Lee, and R.W.Carthew (2007).
Conversion of pre-RISC to holo-RISC by Ago2 during assembly of RNAi complexes.
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17560368 L.Peters, and G.Meister (2007).
Argonaute proteins: mediators of RNA silencing.
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QIP, a putative exonuclease, interacts with the Neurospora Argonaute protein and facilitates conversion of duplex siRNA into single strands.
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Regulatory RNAs: future perspectives in diagnosis, prognosis, and individualized therapy.
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Slicer and the argonautes.
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Epigenetics and microRNAs.
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Molecular basis for target RNA recognition and cleavage by human RISC.
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17310250 S.M.Buker, T.Iida, M.Bühler, J.Villén, S.P.Gygi, J.Nakayama, and D.Moazed (2007).
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Structure of Aquifex aeolicus argonaute highlights conformational flexibility of the PAZ domain as a potential regulator of RNA-induced silencing complex function.
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PDB code: 2nub
17928574 X.Liu, J.K.Park, F.Jiang, Y.Liu, D.McKearin, and Q.Liu (2007).
Dicer-1, but not Loquacious, is critical for assembly of miRNA-induced silencing complexes.
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Biochemical mechanisms of the RNA-induced silencing complex.
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RNAi and microRNAs: from animal models to disease therapy.
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17381277 A.K.Leung, and P.A.Sharp (2006).
Function and localization of microRNAs in mammalian cells.
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16301602 B.A.Kraynack, and B.F.Baker (2006).
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16735068 C.J.Janzen, F.van Deursen, H.Shi, G.A.Cross, K.R.Matthews, and E.Ullu (2006).
Expression site silencing and life-cycle progression appear normal in Argonaute1-deficient Trypanosoma brucei.
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17381284 D.J.Patel, J.B.Ma, Y.R.Yuan, K.Ye, Y.Pei, V.Kuryavyi, L.Malinina, G.Meister, and T.Tuschl (2006).
Structural biology of RNA silencing and its functional implications.
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16931764 D.V.Irvine, M.Zaratiegui, N.H.Tolia, D.B.Goto, D.H.Chitwood, M.W.Vaughn, L.Joshua-Tor, and R.A.Martienssen (2006).
Argonaute slicing is required for heterochromatic silencing and spreading.
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16945958 E.Koller, S.Propp, H.Murray, W.Lima, B.Bhat, T.P.Prakash, C.R.Allerson, E.E.Swayze, E.G.Marcusson, and N.M.Dean (2006).
Competition for RISC binding predicts in vitro potency of siRNA.
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16691418 H.Cerutti, and J.A.Casas-Mollano (2006).
On the origin and functions of RNA-mediated silencing: from protists to man.
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16611939 H.Shi, C.Tschudi, and E.Ullu (2006).
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  RNA, 12, 943-947.  
17053086 H.Shi, C.Tschudi, and E.Ullu (2006).
An unusual Dicer-like1 protein fuels the RNA interference pathway in Trypanosoma brucei.
  RNA, 12, 2063-2072.  
16478716 H.Tsukioka, M.Takahashi, H.Mon, K.Okano, K.Mita, T.Shimada, J.M.Lee, Y.Kawaguchi, K.Koga, and T.Kusakabe (2006).
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  Nucleic Acids Res, 34, 1092-1101.  
17029813 J.S.Parker, and D.Barford (2006).
Argonaute: A scaffold for the function of short regulatory RNAs.
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17381279 J.S.Parker, S.M.Roe, and D.Barford (2006).
Molecular mechanism of target RNA transcript recognition by Argonaute-guide complexes.
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16882972 K.Saito, K.M.Nishida, T.Mori, Y.Kawamura, K.Miyoshi, T.Nagami, H.Siomi, and M.C.Siomi (2006).
Specific association of Piwi with rasiRNAs derived from retrotransposon and heterochromatic regions in the Drosophila genome.
  Genes Dev, 20, 2214-2222.  
17381282 L.Joshua-Tor (2006).
The Argonautes.
  Cold Spring Harb Symp Quant Biol, 71, 67-72.  
16601679 M.Nowotny, and W.Yang (2006).
Stepwise analyses of metal ions in RNase H catalysis from substrate destabilization to product release.
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PDB codes: 2g8f 2g8h 2g8i 2g8k 2g8u 2g8v 2g8w
16308700 M.Schroda (2006).
RNA silencing in Chlamydomonas: mechanisms and tools.
  Curr Genet, 49, 69-84.  
16520821 N.Aronin (2006).
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16778019 N.C.Lau, A.G.Seto, J.Kim, S.Kuramochi-Miyagawa, T.Nakano, D.P.Bartel, and R.E.Kingston (2006).
Characterization of the piRNA complex from rat testes.
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16369554 N.H.Tolia, and L.Joshua-Tor (2006).
Strategies for protein coexpression in Escherichia coli.
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16973001 N.Krishnamurthy, D.P.Brown, D.Kirshner, and K.Sjölander (2006).
PhyloFacts: an online structural phylogenomic encyclopedia for protein functional and structural classification.
  Genome Biol, 7, R83.  
16415015 O.Aparicio, N.Razquin, M.Zaratiegui, I.Narvaiza, and P.Fortes (2006).
Adenovirus virus-associated RNA is processed to functional interfering RNAs involved in virus production.
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Manipulating and enhancing the RNAi response.
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16927374 R.E.Collins, and X.Cheng (2006).
Structural and biochemical advances in mammalian RNAi.
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16882716 S.Dorner, L.Lum, M.Kim, R.Paro, P.A.Beachy, and R.Green (2006).
A genomewide screen for components of the RNAi pathway in Drosophila cultured cells.
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17381332 S.M.Locke, and R.A.Martienssen (2006).
Slicing and spreading of heterochromatic silencing by RNA interference.
  Cold Spring Harb Symp Quant Biol, 71, 497-503.  
16934003 W.J.Meyer, S.Schreiber, Y.Guo, T.Volkmann, M.A.Welte, and H.A.Müller (2006).
Overlapping functions of argonaute proteins in patterning and morphogenesis of Drosophila embryos.
  PLoS Genet, 2, e134.  
16600865 W.Yang, J.Y.Lee, and M.Nowotny (2006).
Making and breaking nucleic acids: two-Mg2+-ion catalysis and substrate specificity.
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The role of PACT in the RNA silencing pathway.
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A potential protein-RNA recognition event along the RISC-loading pathway from the structure of A. aeolicus Argonaute with externally bound siRNA.
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PDB codes: 2f8s 2f8t
16271386 C.Matranga, Y.Tomari, C.Shin, D.P.Bartel, and P.D.Zamore (2005).
Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes.
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A human, ATP-independent, RISC assembly machine fueled by pre-miRNA.
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Small non-coding RNAs as magic bullets.
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Identification of novel argonaute-associated proteins.
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ATP modulates siRNA interactions with an endogenous human Dicer complex.
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siRNA, miRNA and HIV: promises and challenges.
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16081530 N.Baumberger, and D.C.Baulcombe (2005).
Arabidopsis ARGONAUTE1 is an RNA Slicer that selectively recruits microRNAs and short interfering RNAs.
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Ribo-gnome: the big world of small RNAs.
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microRNA-guided posttranscriptional gene regulation.
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Structural domains in RNAi.
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Human RISC couples microRNA biogenesis and posttranscriptional gene silencing.
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16314451 R.S.Pillai (2005).
MicroRNA function: multiple mechanisms for a tiny RNA?
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Silence of the transcripts: RNA interference in medicine.
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Designer siRNAs to overcome the challenges from the RNAi pathway.
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Structure and function of argonaute proteins.
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Design of siRNAs producing unstructured guide-RNAs results in improved RNA interference efficiency.
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16009129 W.Filipowicz (2005).
RNAi: the nuts and bolts of the RISC machine.
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Post-transcriptional gene silencing by siRNAs and miRNAs.
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Biochemical specialization within Arabidopsis RNA silencing pathways.
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Crystal structure of A. aeolicus argonaute, a site-specific DNA-guided endoribonuclease, provides insights into RISC-mediated mRNA cleavage.
  Mol Cell, 19, 405-419.
PDB codes: 1yvu 2ads
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.