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  • 1.
    Johansson, Magnus
    et al.
    Uppsala University.
    Ieong, Ka-Weng
    Uppsala University.
    Trobro, Stefan
    Uppsala University.
    Strazewski, Peter
    Frankrike.
    Åqvist, Johan
    Uppsala University.
    Pavlov, Michael Y.
    Uppsala University.
    Ehrenberg, Måns
    Uppsala University.
    pH-sensitivity of the ribosomal peptidyl transfer reaction dependent on the identity of the A-site aminoacyl-tRNA2011Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, nr 1, 79-84 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We studied the pH-dependence of ribosome catalyzed peptidyl transfer from fMet-tRNA(fMet) to the aa-tRNAs Phe-tRNA(Phe), Ala-tRNA(Ala), Gly-tRNA(Gly), Pro-tRNA(Pro), Asn-tRNA(Asn), and Ile-tRNA(Ile), selected to cover a large range of intrinsic pK(a)-values for the α-amino group of their amino acids. The peptidyl transfer rates were different at pH 7.5 and displayed different pH-dependence, quantified as the pH-value, pK(a)(obs), at which the rate was half maximal. The pK(a)(obs)-values were downshifted relative to the intrinsic pK(a)-value of aa-tRNAs in bulk solution. Gly-tRNA(Gly) had the smallest downshift, while Ile-tRNA(Ile) and Ala-tRNA(Ala) had the largest downshifts. These downshifts correlate strongly with molecular dynamics (MD) estimates of the downshifts in pK(a)-values of these aa-tRNAs upon A-site binding. Our data show the chemistry of peptide bond formation to be rate limiting for peptidyl transfer at pH 7.5 in the Gly and Pro cases and indicate rate limiting chemistry for all six aa-tRNAs.

  • 2.
    Shaw, Jeffrey J.
    et al.
    Johns Hopkins University School of Medicine, Baltimore.
    Trobro, Stefan
    Institutionen för Cell och Molekylärbiologi, Uppsala Universitet.
    He, Shan L.
    Johns Hopkins University School of Medicine, Baltimore.
    Åqvist, Johan
    Institutionen för Cell och Molekylärbiologi, Uppsala Universitet.
    Green, Rachel
    Johns Hopkins University School of Medicine, Baltimore.
    A Role for the 2' OH of peptidyl-tRNA substrate in peptide release on the ribosome revealed through RF-mediated rescue2012Inngår i: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 19, nr 8, 983-993 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 2' OH of the peptidyl-tRNA substrate is thought to be important for catalysis of both peptide bond formation and peptide release in the ribosomal active site. The release reaction also specifically depends on a release factor protein (RF) to hydrolyze the ester linkage of the peptidyl-tRNA upon recognition of stop codons in the A site. Here, we demonstrate that certain amino acid substitutions (in particular those containing hydroxyl or thiol groups) in the conserved GGQ glutamine of release factor RF1 can rescue defects in the release reaction associated with peptidyl-tRNA substrates lacking a 2' OH. We explored this rescue effect through biochemical and computational approaches that support a model where the 2' OH of the P-site substrate is critical for orienting the nucleophile in a hydrogen-bonding network productive for catalysis.

  • 3.
    Trobro, Stefan
    et al.
    Uppsala University.
    Åqvist, Johan
    Uppsala University.
    Mechanism of the translation termination reaction on the ribosome2009Inngår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, nr 47, 11296-303 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ribosomal release factors (RFs) catalyze the termination of protein synthesis by triggering hydrolysis of the peptidyl-tRNA ester bond in the peptidyl transferase center of the ribosome. With new medium-resolution crystallographic structures of RF-ribosome complexes available, it has become possible to examine the detailed mechanism of this process to resolve the key factors responsible for catalysis of the termination reaction. Here, we report computer simulations of the termination reaction that utilize both the new RF complex structures and information from a high-resolution complex with a P-site substrate analogue. The calculations yield a consistent reaction mechanism that reproduces experimental rates and allows us to identify key interactions responsible for the catalytic efficiency. The results are also in general agreement with an earlier model based on molecular docking. The methylated glutamine residue of the universally conserved GGQ motif plays a key role in the hydrolysis reaction by orienting the water nucleophile and by stabilizing the transition state, and its side chain makes an entropic contribution to the lowering of the activation barrier. Two additional water molecules interacting with the P-site substrate are also found to be critically important. Furthermore, the 2'-OH group of the peptidyl-tRNA substrate is predicted to act as a proton shuttle for the leaving group in analogy with the consensus mechanism for peptidyl transfer. Thus, the ribosome's ability to catalyze both the termination (hydrolysis) and peptidyl transfer (aminolysis) reactions is largely explained by this type of unified mechanism, with similar transition states occurring in both processes.

  • 4.
    Wu, Shiying
    et al.
    Department of Cell and Molecular Biology, Uppsala University.
    Chen, Yu
    Department of Cell and Molecular Biology, Uppsala University.
    Mao, Guanzhong
    Department of Cell and Molecular Biology, Uppsala University.
    Trobro, Stefan
    Department of Cell and Molecular Biology, Uppsala University.
    Kwiatkowski, Marek
    Department of Cell and Molecular Biology, Uppsala University.
    Kirsebom, Leif A.
    Department of Cell and Molecular Biology, Uppsala University.
    Transition-state stabilization in Escherichia coli ribonuclease P RNA-mediated cleavage of model substrates2014Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, nr 1, 631-642 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have used model substrates carrying modified nucleotides at the site immediately 5' of the canonical RNase P cleavage site, the -1 position, to study Escherichia coli RNase P RNA-mediated cleavage. We show that the nucleobase at -1 is not essential but its presence and identity contribute to efficiency, fidelity of cleavage and stabilization of the transition state. When U or C is present at -1, the carbonyl oxygen at C2 on the nucleobase contributes to transition-state stabilization, and thus acts as a positive determinant. For substrates with purines at -1, an exocyclic amine at C2 on the nucleobase promotes cleavage at an alternative site and it has a negative impact on cleavage at the canonical site. We also provide new insights into the interaction between E. coli RNase P RNA and the -1 residue in the substrate. Our findings will be discussed using a model where bacterial RNase P cleavage proceeds through a conformational-assisted mechanism that positions the metal(II)-activated H2O for an in-line attack on the phosphorous atom that leads to breakage of the phosphodiester bond.

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