PDBsum entry 1z26

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Gene regulation PDB id
Jmol PyMol
Protein chain
716 a.a. *
Waters ×140
* Residue conservation analysis
PDB id:
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.
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
07-Mar-05     Release date:   05-Apr-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q8U3D2  (Q8U3D2_PYRFU) -  Uncharacterized protein
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.
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

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PDB codes: 3pja 3qb5
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PIWI, piRNAs, and germline stem cells: what's the link?
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Nucleation, propagation and cleavage of target RNAs in Ago silencing complexes.
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PDB codes: 3hjf 3hk2 3hm9 3ho1 3hvr 3hxm
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RISC-target interaction: cleavage and translational suppression.
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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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The Argonaute protein family.
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PDB codes: 3dlb 3dlh
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PDB codes: 2nrr 2nrt 2nrv 2nrw 2nrx 2nrz
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Conversion of pre-RISC to holo-RISC by Ago2 during assembly of RNAi complexes.
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Argonaute proteins: mediators of RNA silencing.
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Slicer and the argonautes.
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Epigenetics and microRNAs.
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PDB code: 2nub
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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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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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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).
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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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17029813 J.S.Parker, and D.Barford (2006).
Argonaute: A scaffold for the function of short regulatory RNAs.
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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.
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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).
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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).
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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).
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16934003 W.J.Meyer, S.Schreiber, Y.Guo, T.Volkmann, M.A.Welte, and H.A.Müller (2006).
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Making and breaking nucleic acids: two-Mg2+-ion catalysis and substrate specificity.
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PDB codes: 2f8s 2f8t
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ATP modulates siRNA interactions with an endogenous human Dicer complex.
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Arabidopsis ARGONAUTE1 is an RNA Slicer that selectively recruits microRNAs and short interfering RNAs.
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Human RISC couples microRNA biogenesis and posttranscriptional gene silencing.
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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.
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PDB code: 1yvu
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.