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The Reaction Coordinate of a Bacterial GH47 α-Mannosidase: A Combined Quantum Mechanical and Structural Approach

Authors

  • Andrew J. Thompson,

    1. Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK)
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  • Dr. Jerome Dabin,

    1. Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK)
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  • Javier Iglesias-Fernández,

    1. Computer Simulation & Modeling Laboratory, Parc Científic de Barcelona, Baldiri Reixac 4, 08028 Barcelona (Spain)
    2. Institut de Química Teòrica i Computacional (IQTCUB) (Spain)
    3. Present address: Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona (Spain)
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  • Dr. Albert Ardèvol,

    1. Computer Simulation & Modeling Laboratory, Parc Científic de Barcelona, Baldiri Reixac 4, 08028 Barcelona (Spain)
    2. Institut de Química Teòrica i Computacional (IQTCUB) (Spain)
    3. Present address: Department of Chemistry and Applied, Biosciences, ETH Zurich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano (Switzerland)
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  • Dr. Zoran Dinev,

    1. School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville (Australia)
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  • Assoc. Prof. Spencer J. Williams,

    1. School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville (Australia)
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  • Dr. Omprakash Bande,

    1. Université de Picardie Jules Vernes, Laboratoire des Glucides (CNRS-FRE 3617), 33, Rue Saint Leu, 80039 Amiens (France)
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  • Dr. Aloysius Siriwardena,

    1. Université de Picardie Jules Vernes, Laboratoire des Glucides (CNRS-FRE 3617), 33, Rue Saint Leu, 80039 Amiens (France)
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  • Carl Moreland,

    1. Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH (UK)
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  • Dr. Ting-Chou Hu,

    1. Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK)
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  • David K. Smith,

    1. Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK)
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  • Prof. Harry J. Gilbert,

    1. Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH (UK)
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  • Prof. Carme Rovira,

    Corresponding author
    1. Computer Simulation & Modeling Laboratory, Parc Científic de Barcelona, Baldiri Reixac 4, 08028 Barcelona (Spain)
    2. Institut de Química Teòrica i Computacional (IQTCUB) (Spain)
    3. Present address: Departament de Química Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona (Spain)
    4. Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08020 Barcelona (Spain)
    • Computer Simulation & Modeling Laboratory, Parc Científic de Barcelona, Baldiri Reixac 4, 08028 Barcelona (Spain)
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  • Prof. Gideon J. Davies

    Corresponding author
    1. Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK)
    • Department of Chemistry, University of York, Heslington, York, YO10 5DD (UK)
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  • We thank the UK Biotechnology and Biological Sciences Research Council (BBSRC), the Spanish Ministry of Economy and Competitiveness (MINECO, CTQ2011-25871), and the Generalitat de Catalunya (2009SGR-1309). A.S. thanks the Indo-French Centre for the Promotion of Advance Research (IFCPAR/CEFIPRA) for funding and for a postdoctoral fellowship (to O.B.). A.A. acknowledges a long-term fellowship from the European Molecular Biology Organization (EMBO). We acknowledge the computer support, technical expertise, and assistance provided by the Barcelona Supercomputing Center: Centro Nacional de Supercomputación (BSC-CNS).

Abstract

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Mannosides in the southern hemisphere: Conformational analysis of enzymatic mannoside hydrolysis informs strategies for enzyme inhibition and inspires solutions to mannoside synthesis. Atomic resolution structures along the reaction coordinate of an inverting α-mannosidase show how the enzyme distorts the substrate and transition state. QM/MM calculations reveal how the free energy landscape of isolated α-D-mannose is molded on enzyme to only allow one conformationally accessible reaction coordinate.

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