Small Molecule Binding, Docking, and Characterization of the Interaction between Pth1 and Peptidyl-tRNA

Hames, Mary C.; McFeeters, Hana; Holloway, W. Blake; Stanley, Christopher B.; Urban, Volker S.; McFeeters, Robert L.

doi:10.3390/ijms141122741

Cited by 10 publications

(11 citation statements)

References 42 publications

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“…The minor groove of the TψC arm has been shown to interact with helix α6 (Ito et al 2012), while the acceptor-CCA end has been proposed to be clamped by K146. Hames et al (2013) have studied Pth-peptidyl-tRNA complex with SANS and have developed a low resolution model in which, unlike the Pth-CCA-acceptor-TψC crystal structure, there is an end to end interaction and almost no overlap between the Pth and tRNA regions. This has been suggested to reflect a later step in the reaction, i.e., a pre-product dissociation complex.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the stereochemical and dynamic aspects of the catalytic site of bacterial peptidyl-tRNA hydrolase

Kabra

Shahid

Pal

et al. 2016

RNA

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Bacterial peptidyl-tRNA hydrolase (Pth; EC 3.1.1.29) hydrolyzes the peptidyl-tRNAs accumulated in the cytoplasm and thereby prevents cell death by alleviating tRNA starvation. X-ray and NMR studies of Vibrio cholerae Pth (VcPth) and mutants of its key residues involved in catalysis show that the activity and selectivity of the protein depends on the stereochemistry and dynamics of residues H24, D97, N118, and N14. D97-H24 interaction is critical for activity because it increases the nucleophilicity of H24. The N118 and N14 have orthogonally competing interactions with H24, both of which reduce the nucleophilicity of H24 and are likely to be offset by positioning of a peptidyl-tRNA substrate. The region proximal to H24 and the lid region exhibit slow motions that may assist in accommodating the substrate. Helix α3 exhibits a slow wobble with intermediate time scale motions of its N-cap residue N118, which may work as a flypaper to position the scissile ester bond of the substrate. Overall, the dynamics of interactions between the side chains of N14, H24, D97, and N118, control the catalysis of substrate by this enzyme.

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Section: Introductionmentioning

confidence: 99%

Unraveling the stereochemical and dynamic aspects of the catalytic site of bacterial peptidyl-tRNA hydrolase

Kabra

Shahid

Pal

et al. 2016

RNA

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“…To avoid excessive build-up of peptidyl-tRNAs and resulting tRNA starvation, it is vital for cells to maintain peptidyl-tRNA hydrolase (Pth) activity [ 5 ]. Two distinct classes of Pth enzymes are known, with Pth1 originally found in bacteria and Pth2 found predominantly in archaea and eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1

et al. 2016

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Peptidyl-tRNA hydrolases (Pths) play ancillary yet essential roles in protein biosynthesis by recycling peptidyl-tRNA. In E. coli, inhibition of bacterial Pth1 leads to accumulation of peptidyl-tRNA, depletion of aminoacyl-tRNA, and cell death. Eukaryotes have multiple Pths and Pth1 knock out was shown to have no effect on viability in yeast. Thereby, bacterial Pth1 is a promising target for novel antibiotic development. With the abundance of Pth1 structural data, molecular docking was used for virtual screening of existing, commercially available antibiotics to map potential interactions with Pth enzymes. Overall, 83 compounds were docked to eight different bacterial Pth1 and three different Pth2 structures. A variety of compounds demonstrated favorable docking with Pths. Whereas, some compounds interacted favorably with all Pths (potential broad spectrum inhibition), more selective interactions were observed for Pth1 or Pth2 and even specificity for individual Pth1s. While the correlation between computational docking and experimentation still remains unknown, these findings support broad spectrum inhibition, but also point to the possibility of narrow spectrum Pth1 inhibition. Also suggested is that Pth1 can be distinguished from Pth2 by small molecule inhibitors. The findings support continued development of Pth1 as an antibiotic target.

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“…Helping to explain the low affinity, 13 also bound to at least one other site on Pth1, in part the same secondary site which did not affect enzyme activity for a previously reported synthetic inhibitor. 20 While not promising for clinical application, these findings represent the first reported small molecule natural product inhibitor of bacterial Pth1, which to date has been limited to crude natural product extracts. 27,28 Therefore these compounds provide tools to expand our understanding of Pth1 inhibition.…”

Section: Antimicrobial Activitymentioning

confidence: 96%

“…Bacterial Pth1 represents a promising new target for antibiotic development 19 for which little is known about small molecule inhibition. 20 Based on this initial screening set, secondary metabolites from fungal cultures could serve as a source of Pth1 inhibitors, providing avenues to better understand inhibitor binding and inhibitor bound states.…”

Section: Introductionmentioning

confidence: 99%

α-Pyrone derivatives, tetra/hexahydroxanthones, and cyclodepsipeptides from two freshwater fungi

El‐Elimat

Raja

Day

et al. 2017

Bioorganic & Medicinal Chemistry

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Eighteen (1-18) and seven (1, 4, 6-8, 17 and 18) compounds were isolated from organic extracts of axenic cultures of two freshwater fungi Clohesyomyces sp. and Clohesyomyces aquaticus (Dothideomycetes, Ascomycota), respectively. Compounds 1-12 belong to the α-pyrone class of natural products, compounds 13 and 14 were tetrahydroxanthones, compounds 15 and 16 were hexahydroxanthones, while compounds 17 and 18 were cyclodepsipeptides. The structures were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configurations of compounds 2, 3, 6, and 7 were assigned via a modified Mosher's ester method using H NMR data. The relative configurations of compounds 14-16 were determined through NOE data. Compounds 1, 2, 6, 8, 13, 14, and 15 were found to inhibit the essential enzyme bacterial peptidyl-tRNA hydrolase (Pth1), with (13; secalonic acid A) being the most potent. Compounds 1 and 4-18 were also evaluated for antimicrobial activity against an array of bacteria and fungi but were found to be inactive.

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Small Molecule Binding, Docking, and Characterization of the Interaction between Pth1 and Peptidyl-tRNA

Cited by 10 publications

References 42 publications

Unraveling the stereochemical and dynamic aspects of the catalytic site of bacterial peptidyl-tRNA hydrolase

Unraveling the stereochemical and dynamic aspects of the catalytic site of bacterial peptidyl-tRNA hydrolase

Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1

α-Pyrone derivatives, tetra/hexahydroxanthones, and cyclodepsipeptides from two freshwater fungi

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