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    TraduccinEl ribosoma es una ribozima!!

    3 acidos nucleicos :mRNA, rRNA, tRNA

    Tamao relativo del ribosoma y los

    tRNAs, y el mensajero

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    Qu es una ribozima?

    Schematic (A) and ribbon (B) diagrams depicting the crystalstructure of the full-length hammerhead ribozyme. Thesequence and secondary structure in Figure A is color-codedto match the structural features shown in Figure B. Thecleavage site nucleotide, C-17, is shown in green, and varioushelical stems and loops are denoted using several other colors.Tertiary hydrogen bonding contacts are denoted as thin blacklines, and tertiary stacking interactions as thin green lines. SeeFigure 2 for a detailed schematic representation of the active

    site.

    Figure 2 A proposed mechanism for hammerhead ribozyme catalysis. The

    nucleotide implicated as a general base in the self-cleavage reaction, G-12, isshown in red. The nucleotide implicated in general acid catalysis, G-8, is shownin dark blue. The substrate RNA is black, and water molecules that mayparticipate in the reaction, playing the roles of specific base and specific acidcatalysts, are shown in magenta and cyan. The scissile phosphate is depicted asan (unobserved) pentacoordinated oxyphosphorane. G-12 can abstract a protonfrom the 2'-OH of the cleavage-site ribose only if the endocyclic nitrogen N1becomes deprotonated (as shown). This may happen via simple ionization, orthrough a (rare and transient) tautomerization to the enolic form (as shown). Asthe 2'-proton (in yellow) is abstracted by G-12, the bond between the 2'O and thephosphorus atom forms, and that between the phosphorus and the 5'O begins tobreak. As the latter breaks, a negative charge accumulates on the leaving group5'O. A proton relay may then take place in which the 5'O acquires the 2'-protonfrom G-8, which is simultaneously replaced with that from an adjacent watermolecule or hydronium ion (as shown).

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    Ribosomas y particulas ribonucleoproteina

    Ribosomas rRNAs Proteinas

    Bacteriana (70S) 23 S=2904 bases 3166% RNA 5 S = 120 bases2.5 MDa

    50 y 30 S 16S= 1542 bases 21-------------------------------------------------------------------------------Mamiferos (80S) 28S = 4718 bases60% RNA 5.8 S = 160 bases 494.2 MDa 5 S= 120 bases

    18S =1874 bases 33

    Llevan a cabo la formacion del enlace peptidico, pero son en su mayor parteAcidos nucleicos!!

    2.5 MD 2500 KDa (T7= 90, RNAP= 500)

    Insulin 5.8 KDa

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    ElongacionBastante bien estudiado en procariontes

    Factor Prokaryotes Eukaryotesinitiator tRNA fMet Metlarge subunit 50S (23S and 5S rRNA) 60S (28S, 5S, and 5.8S rRNA)(35 proteins) (49 proteins)small subunit 30S (16S rRNA) 40S (18S rRNA)

    (21 proteins ) (33 proteins)ribosome 70S 80S

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    No tanta diferencia en tamao entre bacteria y eucariontes

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    Sintesis de polipeptidos

    5-m7GpppNNNNNNNNNNACCAUGGCAGUUCCAGCUAGCGAUNNN-3Met Ala Val Pro Ala Ser AspNH3- -COOH

    Los mRNAs se leen en la direccion de 5 a 3 primo

    La sintesis de proteinas es del extremo amino al carboxilo terminal

    codon (codes for 1 of 20 amino acids)

    Como se lleva a cabo la reaccion?

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    Los triplesExisten 4 bases (A, C, G, and U)La historia de Gamow codigo de 1 nucleotido 41 = 4 amino acidosCodigo de 2 nucleotidos 42 = 16 amino acidos Codigo de 3 nucletotidos 43 = 64 amino acidosEl codigo del triple es el mas pequeo para los 20 aminoacidosCual de los siguientes procesos no se lleva a cabo de 5 a 3primo

    a) Replicacionb) Sintesis quimica de DNAc) Transcripciond) Translacion

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    El codigo de los trip letes1961-Marshall Nirenberg and Johann Heinrich Matthaei

    5-UUUUUUUUUUUUUUUUUUUUUUUUU-3Phe Phe Phe Phe

    Gobind Khorana

    5-UCUCUCUCUCUCUCUCUCUCUCUCU-3Ser Leu Ser Leuepeateddinucleotide

    if the codon was 2 or 4 nt then the protein would be a homopolypeptide

    5-UUCUUCUUCUUCUUCUUCUUCUUC-3Phe Phe Phe Phe

    repeatedtrinucleotide Ser Ser Ser SerLeu Leu Leu Leu

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    Incorporation of 14Clabeled valine into protein in Escherichia coli extracts. Endogenousincorporation of radioactive amino acids into protein in E. coli extracts was high. However, aminoacid incorporation ceased after incubation for ~40 min with DNase I. I found that I could freeze E.coli extracts and thaw them without loss of activity, so I incubated E. coli extracts in the absenceof radioactive amino acids for 40 min, divided the extracts into small aliquots and froze them foruse later in different experiments. Endogenous incorporation of radioactive amino acids was

    greatly reduced in such extracts, and addition of mRNA preparations from ribosomes clearlystimulated amino acid incorporation into protein [16, 34 and 49]. Reproduced from Ref. [16].

    Heinrich MatthaeiHeinrich Matthaei

    Marshall Nirenberg

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    Poly(U) greatly stimulates the incorporation of radioactive phenylalanine into poly-

    phenylalanine [8]. Addition of poly(A) completely inhibits the mRNA activity of

    poly(U) by the formation of double-stranded and triple-stranded helices. By contrast,

    addition of poly(C) has little effect on the mRNA activity of poly(U). This experiment,

    done in 1961, was the first the anti-sense RNA experiment [8].

    http://lib3.tufts.edu:2061/science?_ob=ArticleURL&_udi=B6TCV-4B84YVY-1&_coverDate=12%2F18%2F2003&_rdoc=1&_fmt=full&_orig=search&_sort=d&view=c&_acct=C000014058&_version=1&_urlVersion=0&_userid=201547&md5=5968db711645e2daf770de1b19a044b8http://lib3.tufts.edu:2061/science?_ob=ArticleURL&_udi=B6TCV-4B84YVY-1&_coverDate=12%2F18%2F2003&_rdoc=1&_fmt=full&_orig=search&_sort=d&view=c&_acct=C000014058&_version=1&_urlVersion=0&_userid=201547&md5=5968db711645e2daf770de1b19a044b8http://lib3.tufts.edu:2061/science?_ob=ArticleURL&_udi=B6TCV-4B84YVY-1&_coverDate=12%2F18%2F2003&_rdoc=1&_fmt=full&_orig=search&_sort=d&view=c&_acct=C000014058&_version=1&_urlVersion=0&_userid=201547&md5=5968db711645e2daf770de1b19a044b8http://lib3.tufts.edu:2061/science?_ob=ArticleURL&_udi=B6TCV-4B84YVY-1&_coverDate=12%2F18%2F2003&_rdoc=1&_fmt=full&_orig=search&_sort=d&view=c&_acct=C000014058&_version=1&_urlVersion=0&_userid=201547&md5=5968db711645e2daf770de1b19a044b8
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    The specificity of randomly ordered polynucleotide templates in

    stimulating amino acid incorporation into protein in Escherichia

    coli extracts. Only the minimum kinds of bases necessary for

    template activity are shown, so many amino acids that respond

    to randomly ordered polynucleotides composed of two or more

    kinds of bases are omitted. The base compositions of RNA

    codons were derived from these experiments [49]. Reproducedfrom Ref. [49].

    The theoretical frequencies of RNA codons in randomly ordered poly(AC) preparations that contain

    different proportions of A and C, compared with the observed frequencies of incorporation of

    radioactively labeled amino acids into protein. The codon for histidine contains one A and two Cs,

    and the codons for asparagine and glutamine contain two As and one C. These results showed that

    the code is a triplet code [18 and 19]. Reproduced from Ref. [18].

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    The hydrophobic amino acids Phe, Leu, Ile, Met and Val correspond to chemically similar codons that

    have U as the second base. By contrast, the hydrophilic amino acids Tyr, His, Gln, Asn, Lys, Asp and Glu

    correspond to codons with A as the second base. In addition, amino acids with chemically similar side

    chains, such as Asp and Glu, and Asn and Gln, have chemically similar codons. Clearly, the arrangement

    of codons and amino acids is not random.

    It took us about a year to synthesize the 64

    trinucleotides and test each against 20

    radioactive aminoacyl-tRNA preparations todetermine the nucleotide sequences of RNA

    codons [30, 33, 35, 36, 37, 38, 39 and 40].

    Gobind Khorana and his colleagues synthesized

    the 64 trinucleotides chemically and also

    determined nucleotide sequences of some RNA

    codons [44]. The green AUG corresponds to

    methionine and N-formyl-methionine tRNA, an

    initiator of protein synthesis [45]. The red

    codons specify the termination of protein

    synthesis [46, 47 and 48].

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    RNA de transferencia

    Como es que un triplete especifica la identidad de un amino acido?

    El papel de tRNA (RNA de transferencia)

    El tRNA se enlaza a su correspondiente amino acido y se llamaamino acil tRNA y la adicion de los amino acidos al tRNA es llevadaa cabo por la aminoacyl tRNA sintetasa

    Para cada uno de los 20 amino acidos hay una aminoacyl tRNA

    sintetasa y uno o mas tRNAs

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    Transfer RNA is unique among nucleic acids in itscontent of "unusual" bases. An unusual base is anypurine or pyrimidine ring except the usual A, G, C, andU from which all RNAs are synthesized. All other basesare produced by modification of one of the four basesafter it has been incorporated into the

    polyribonucleotide chain

    El 3 del tRNA se genera al cortarse y

    Adicionarse CCA

    http://www.ergito.com/441http://www.ergito.com/441
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    (anticodon)

    CCA Carga de los

    amino acidos

    Secuencia CCAAnticodon; aparea con el mRNA (codon)

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    Existen 61 different codons ysolamente 40 tRNAs.

    La hipotesis de wobblehypothesis : en la tercera posicionse puede formar un par

    no standar inosine se aparea con 3bases

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    The wobble position

    Phe

    Phe Leu

    Leu

    aminoacyl-tRNA

    El mismo aminoacyl-tRNA reconoce multiples codones

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    Wobble base pairsanticodon(first base)codon(third base)

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    AMINO ACIL tRNA sintetasas

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    Dos sitios activos en la edicion y sintesisde tRNAs

    Class I (Glu-tRNA synthetase)/

    Class II (Asp-tRNA synthetase)

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    Los ribososomas tienen 3

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    Los ribososomas tienen 3sitios de union al tRNA

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    A site :el aminoacyl-tRNA entrante se apareacon el codonP site: Es el sitio ocupado por el peptidyl-tRNA,

    el tRNA que lleve el polipeptido nascenteE site: Exit

    Los ribosomas tienen 3 sitios:

    A site: acceptor el

    aminoacyl-tRNA se enlaza alcondon del mRNA

    P site: donde se ubica el tRNAque elonga la cadena

    polipetidica E site: donde el tRNA sale del

    ribosoma

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    Iniciacin Empieza en el codon AUG

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    p

    En bacteria se tiene el sitio de union a ribosoma (secuencia Shine-Dalgarno) quees complementaria a una secuencia del RNA ribosomal de la subunidadpequea

    Este sitio tiene la secuencia 5'-AGGAGGU-3' y se localiza ~6 nucleotidos rioarriba del AUG inicial

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    Aminoacylated tRNAs occupy the P and A sites

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    En bacteria se necesita de los 3Factores IF-1, IF-2 y IF-3

    Once the small ribosomal subunit isbound to the mRNA, the aminoacylinitiator tRNA binds to the AUG sequence.The initiator methionine is modified with aformyl group and is called N-formylmethionine.

    LA INICIACION REQUERIE DE FACTORES

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    Elongacion

    Al principio de la elongacion, el tRNA

    iniciador se encuentra en el sitio P, y lossitios E y A se encuentran vacios. El

    aminoacyl tRNA se enlaza al codon en el

    sitio A y se lleva a cabo la formacion delenlace peptidico

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    El factor de elongacion Tu carga a los aminoacyl-tRNA en el sitio A

    Tu

    Unido al GTP o al GDP

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    EF-Tu directs binding of aminoacyl-tRNAs at the A site

    gunanine nucleotide exchangefactor for EF-Tu

    ternary complex

    ribosome-dependent GTPaseactivity of EF-Tu

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    13 Elongation factors bind alternately to the ribosome

    EF-G structure mimicsaminacyl-tRNA

    EF factors have alternating interactions

    Fid lid d l i

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    Fidelidad elongacion

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    Termination codons are recognized by protein factors

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    Several factors have similar shapeseRF1 mimics tRNA

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    EukaryoteseRF1 mimics a tRNA

    Partic ipates in the hydrolysis of the ester bond between the peptide and the tRNAIn the neighbor ing peptidyl-tRNA in the P site of the ribosome

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    Requerimentos de energia de la traduccion

    Step Event Energyamino acid activation 1 ATP

    Initiation inactive 80S ribosomedissociation -mRNA binding to 40S subunit -assembly of 40S and 60S subunits -

    Elongation binding of aminoacyl-tRNA 1 GTP (EF-Tu)peptide bond formation exergonictranslocation 1 GTP (EF-G)

    Termination 1 GTP (RF-3)1 ATP + 3 GTP / cycle

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    Yusupov et al. Science292, 883 (2001)

    Estructura secundaria del RNA ribosomal

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    Cryo-EM map of the E. co l i 70S ribosome

    Gabashvili et al. Cell100, 537 (2000)

    X-ray structure of the 70S ribosome from T. therm op hilu s

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    Yusupov et al. Science292, 883 (2001)

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    X-ray structure: tRNA binding sites

    Yusupov et al. Science292, 883 (2001)

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    12 intersubunit contacts hold together the 70S ribosome

    Yusupov et al. Science292, 883 (2001)

    Magenta: RNA-RNA contactsYellow: protein-protein and protein-RNA contacts

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    The elongation process: thepeptidyl transferase center

    Schmeing et al. Nat. Struct. Biol. 9, 225-230 (2002)

    deacetylated tRNA analogue:CCAdeacetylated tRNAanalogue:CCApeptidyl tRNA analogue:puromycin-Phe-caproic acid-biotin

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    tRNA-ribosome interactions

    Yusupov et al. Science292, 883 (2001)

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    Elongation: decoding of the mRNA

    Ogle et al. Science292, 897-902 (2001)

    Conservation in the 50S subunit

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    RNA: shown in space f il ling spheres Blue: conserved RNA in al l speciesProtein: shown as ribbons Green: non-conserved RNAMoore and Steitz, Nature418, 229-235 (2002)

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    One of the A-sitesubstrates, cytidine-cytidine-hydroxypuromycin (CChPmn),

    includes C74; the other, ChPmn, does not.

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    Themechanismb

    yw

    hichtheribosome

    protectsthepeptidyltRNA

    fromh

    ydrolysiscanb

    eunderstoodbyinspectingthecon

    formation

    ofthepeptidyl-tRNA

    analogueboundtothelargeribosom

    al

    subunit.

    Como se evita lahidrlisis?

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    Cienciabsica

    yantibioticos

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    vo

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    Elstoduodoabocoeeestoa

    Steitz, T. A. and Moore, P. B. Trends Bio. Sci. 28, 411-418 (2003)

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    V

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    New antibiotics for Serious Drug Resistant Infections

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    New antibiotics for Serious Drug Resistant Infections

    Recent Rib-X News09/13/10

    Rib-X Pharmaceuticals Presents Data SupportingDelafloxacin as a Potential Best-in-class Fluoroquinoloneat ICAAC

    09/13/10

    Rib-X Pharmaceuticals' Nobel Prize Winning Structure-based Design and Optimization Platform to be Featuredin a Symposium Reviewing 50 Years of Antibiotic DrugDiscovery at the 50th ICAAC Meeting

    About UsRib-X Pharmaceuticals, Inc., is a product-driven small-molecule drug discovery and development company focusedon developing and commercializing antibiotics to treat highly-

    resistant bacterial infections.Read MoreQuick Link to Pubs and Posters

    PipelineDelafloxacinRadezolidR-02R-04

    Experimentos para determinar la estructura del ribosomaMicroscopia electronicaCristalizacion

    A. Yonath, Weizman Institute of Science, Isreal

    V. Ramakrishnan, MRC Lab of Molecular Biology, EnglandT. Steitz, Yale University, USA

    U d hi i

    http://www.rib-x.com/news_and_events/press_releaseshttp://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/about_ushttp://www.rib-x.com/about_ushttp://www.rib-x.com/r_and_d/publications_and_presentationshttp://www.rib-x.com/pipelinehttp://www.rib-x.com/pipeline/rx_3341http://www.rib-x.com/pipeline/rx_1741http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_04http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_02http://www.rib-x.com/pipeline/rx_1741http://www.rib-x.com/pipeline/rx_3341http://www.rib-x.com/pipelinehttp://www.rib-x.com/r_and_d/publications_and_presentationshttp://www.rib-x.com/about_ushttp://www.rib-x.com/about_ushttp://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_13http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/release_2010_09_14http://www.rib-x.com/news_and_events/press_releaseshttp://www.rib-x.com/news_and_events/press_releaseshttp://www.rib-x.com/news_and_events/press_releaseshttp://www.rib-x.com/news_and_events/press_releases
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    Un poco de historia

    Yonath

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    Steitz

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    The Steitz group utilized the

    TaBr, W11Rh, and W18Asclusters to successfully phasethe structure of the large 50Sribosomal subunit at low resolution

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