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  1. Article ; Online: Molecular Dynamics and Docking Simulations of Homologous RsmE Methyltransferases Hints at a General Mechanism for Substrate Release upon Uridine Methylation on 16S rRNA

    Aaron Hernández-Cid / Jorge Lozano-Aponte / Thomas Scior

    International Journal of Molecular Sciences, Vol 24, Iss 23, p

    2023  Volume 16722

    Abstract: In this study, molecular dynamics (MD) and docking simulations were carried out on the crystal structure of Neisseria Gonorrhoeae RsmE aiming at free energy of binding estimation (ΔG binding ) of the methyl transfer substrate S-adenosylmethionine (SAM), ... ...

    Abstract In this study, molecular dynamics (MD) and docking simulations were carried out on the crystal structure of Neisseria Gonorrhoeae RsmE aiming at free energy of binding estimation (ΔG binding ) of the methyl transfer substrate S-adenosylmethionine (SAM), as well as its homocysteine precursor S-adenosylhomocysteine (SAH). The mechanistic insight gained was generalized in view of existing homology to two other crystal structures of RsmE from Escherichia coli and Aquifex aeolicus . As a proof of concept, the crystal poses of SAM and SAH were reproduced reflecting a more general pattern of molecular interaction for bacterial RsmEs. Our results suggest that a distinct set of conserved residues on loop segments between β12, α6, and Met169 are interacting with SAM and SAH across these bacterial methyltransferases. Comparing molecular movements over time (MD trajectories) between Neisseria gonorrhoeae RsmE alone or in the presence of SAH revealed a hitherto unknown gatekeeper mechanism by two isoleucine residues, Ile171 and Ile219. The proposed gating allows switching from an open to a closed state, mimicking a double latch lock. Additionally, two key residues, Arg221 and Thr222, were identified to assist the exit mechanism of SAH, which could not be observed in the crystal structures. To the best of our knowledge, this study describes for the first time a general catalytic mechanism of bacterial RsmE on theoretical ground.
    Keywords methyltransferase ; 16S rRNA methylation ; RsmE ; molecular dynamics ; antimicrobial resistance ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2023-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Three-dimensional mapping of differential amino acids of human, murine, canine and equine TLR4/MD-2 receptor complexes conferring endotoxic activation by lipid A, antagonism by Eritoran and species-dependent activities of lipid IVa in the mammalian LPS sensor system

    Julian A. Yunes-Rojas / Vianihuini Figueroa-Vazquez / Jorge Lozano-Aponte / Thomas Scior / Ulrich Zähringer / Christian Alexander

    Computational and Structural Biotechnology Journal, Vol 7, Iss 9, p e

    2013  Volume 201305003

    Abstract: A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. ... ...

    Abstract A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. coli -type lipid A and its precursor lipid IVA regarding human, murine, equine and canine species. To this end, their sequences and structures of hitherto known Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD-2) complexes were aligned and their differential side chain patterns studied. If required due to the lack of the corresponding X-ray crystallographic data, three-dimensional models of TLR4/MD-2/ligand complexes were generated using mono and dimeric crystal structures as templates and in silico docking of the prototypic ligands lipid A, lipid IVA and Eritoran. All differential amino acids were mapped to pinpoint species dependency on an atomic scale, i.e. the possible concert of mechanistically relevant side chains. In its most abstract and general form the three-dimensional (3D-) models devise a triangular interface or “wedge” where molecular interactions between TLR4, MD-2 and ligand itself take place. This study identifies two areas in the wedge related to either agonism or antagonism reflecting why ligands like lipid IVA can possess a species dependent dual activity. Lipid IVA represents an imperfect (underacylated and backbone-flipped), low affinity ligand of mammalian TLR4/MD-2 complexes. Its specific but weak antagonistic activity in the human system is in particular due to the loss of phosphate attraction in the wedge-shaped region conferred by nonhomologous residue changes when compared to crystal and modeled structures of the corresponding murine and equine TLR4/MD-2 complexes. The counter-TLR4/MD-2 unit was also taken into account since agonist-mediated dimerization in a defined m-shaped complex composed of two TLR4/MD-2/agonist subunits triggers intracellular signaling during the innate immune response to bacterial endotoxin exposure.
    Keywords Toll-like receptors ; MD-2 ; lipopolysaccharide ; molecular modeling ; docking ; Biotechnology ; TP248.13-248.65 ; Chemical technology ; TP1-1185 ; Technology ; T ; DOAJ:Biotechnology ; DOAJ:Life Sciences ; DOAJ:Biology and Life Sciences
    Subject code 540
    Language English
    Publishing date 2013-05-01T00:00:00Z
    Publisher Research Network of Computational and Structural Biotechnology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Three-dimensional mapping of differential amino acids of human, murine, canine and equine tlr4/md-2 receptor complexes conferring endotoxic activation by lipid a, antagonism by eritoran and species-dependent activities of lipid iva in the mammalian lps sensor system

    Scior, Thomas / Jorge Lozano-Aponte / Vianihuini Figueroa-Vazquez / Julian A. Yunes-Rojas / Ulrich Zähringer / Christian Alexander

    Research Network of Computational and Structural Biotechnology Computational and Structural Biotechnology Journal. 2013 May, v. 7

    2013  

    Abstract: A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. ... ...

    Abstract A literature review concerning the unexpected species differences of the vertebrate innate immune response to lipid IVA was published in CSBJ prior to the present computational study to address the unpaired activity-sequence correlation of prototypic E. coli -type lipid A and its precursor lipid IVA regarding human, murine, equine and canine species. To this end, their sequences and structures of hitherto known Toll-like receptor 4 (TLR4) and myeloid differentiation factor 2 (MD-2) complexes were aligned and their differential side chain patterns studied. If required due to the lack of the corresponding X-ray crystallographic data, three-dimensional models of TLR4/MD-2/ligand complexes were generated using mono and dimeric crystal structures as templates and in silico docking of the prototypic ligands lipid A, lipid IVA and Eritoran. All differential amino acids were mapped to pinpoint species dependency on an atomic scale, i.e. the possible concert of mechanistically relevant side chains. In its most abstract and general form the three-dimensional (3D-) models devise a triangular interface or “wedge” where molecular interactions between TLR4, MD-2 and ligand itself take place. This study identifies two areas in the wedge related to either agonism or antagonism reflecting why ligands like lipid IVA can possess a species dependent dual activity. Lipid IVA represents an imperfect (underacylated and backbone-flipped), low affinity ligand of mammalian TLR4/MD-2 complexes. Its specific but weak antagonistic activity in the human system is in particular due to the loss of phosphate attraction in the wedge-shaped region conferred by nonhomologous residue changes when compared to crystal and modeled structures of the corresponding murine and equine TLR4/MD-2 complexes. The counter-TLR4/MD-2 unit was also taken into account since agonist-mediated dimerization in a defined m-shaped complex composed of two TLR4/MD-2/agonist subunits triggers intracellular signaling during the innate immune response to bacterial endotoxin exposure.
    Keywords Escherichia coli ; Toll-like receptor 4 ; X-ray diffraction ; amino acids ; antagonism ; crystal structure ; dimerization ; dogs ; endotoxins ; horses ; humans ; innate immunity ; interspecific variation ; ligands ; lipid A ; mice ; molecular models ; phosphates
    Language English
    Dates of publication 2013-05
    Size p. e201305003.
    Publishing place Elsevier B.V.
    Document type Article
    ISSN 2001-0370
    DOI 10.5936/csbj.201305003
    Database NAL-Catalogue (AGRICOLA)

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