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Intrinsic motions along an enzymatic reaction trajectory

Author

Listed:
  • Katherine A. Henzler-Wildman

    (Department of Biochemistry and Howard Hughes Medical Institute,)

  • Vu Thai

    (Department of Biochemistry and Howard Hughes Medical Institute,)

  • Ming Lei

    (Department of Biochemistry and Howard Hughes Medical Institute,)

  • Maria Ott

    (Institute of Physics, Martin Luther-University Halle-Wittenberg, D-06120 Halle, Germany)

  • Magnus Wolf-Watz

    (Department of Biochemistry and Howard Hughes Medical Institute,
    Present addresses: University of Umeå, Department of Chemistry, SE-90187 Umeå, Sweden (M.W.-W.); Departments of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (T.F.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA (E.P.); Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA (M.A.W.); University at Lübeck, Institute of Physics, 23538 Lübeck, Germany (C.G.H.).)

  • Tim Fenn

    (Brandeis University, Waltham, Massachusetts 02454, USA
    Present addresses: University of Umeå, Department of Chemistry, SE-90187 Umeå, Sweden (M.W.-W.); Departments of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (T.F.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA (E.P.); Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA (M.A.W.); University at Lübeck, Institute of Physics, 23538 Lübeck, Germany (C.G.H.).)

  • Ed Pozharski

    (Brandeis University, Waltham, Massachusetts 02454, USA
    Present addresses: University of Umeå, Department of Chemistry, SE-90187 Umeå, Sweden (M.W.-W.); Departments of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (T.F.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA (E.P.); Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA (M.A.W.); University at Lübeck, Institute of Physics, 23538 Lübeck, Germany (C.G.H.).)

  • Mark A. Wilson

    (Brandeis University, Waltham, Massachusetts 02454, USA
    Present addresses: University of Umeå, Department of Chemistry, SE-90187 Umeå, Sweden (M.W.-W.); Departments of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (T.F.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA (E.P.); Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA (M.A.W.); University at Lübeck, Institute of Physics, 23538 Lübeck, Germany (C.G.H.).)

  • Gregory A. Petsko

    (Brandeis University, Waltham, Massachusetts 02454, USA)

  • Martin Karplus

    (Harvard University, Cambridge, Massachusetts 02138, USA
    Laboratoire de Chimie Biophysique, ISIS, Université Louis Pasteur)

  • Christian G. Hübner

    (Institute of Physics, Martin Luther-University Halle-Wittenberg, D-06120 Halle, Germany
    Present addresses: University of Umeå, Department of Chemistry, SE-90187 Umeå, Sweden (M.W.-W.); Departments of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA (T.F.); Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA (E.P.); Department of Biochemistry and the Redox Biology Center, University of Nebraska, Lincoln, Nebraska 68588, USA (M.A.W.); University at Lübeck, Institute of Physics, 23538 Lübeck, Germany (C.G.H.).)

  • Dorothee Kern

    (Department of Biochemistry and Howard Hughes Medical Institute,)

Abstract

The mechanisms by which enzymes achieve extraordinary rate acceleration and specificity have long been of key interest in biochemistry. It is generally recognized that substrate binding coupled to conformational changes of the substrate–enzyme complex aligns the reactive groups in an optimal environment for efficient chemistry. Although chemical mechanisms have been elucidated for many enzymes, the question of how enzymes achieve the catalytically competent state has only recently become approachable by experiment and computation. Here we show crystallographic evidence for conformational substates along the trajectory towards the catalytically competent ‘closed’ state in the ligand-free form of the enzyme adenylate kinase. Molecular dynamics simulations indicate that these partially closed conformations are sampled in nanoseconds, whereas nuclear magnetic resonance and single-molecule fluorescence resonance energy transfer reveal rare sampling of a fully closed conformation occurring on the microsecond-to-millisecond timescale. Thus, the larger-scale motions in substrate-free adenylate kinase are not random, but preferentially follow the pathways that create the configuration capable of proficient chemistry. Such preferred directionality, encoded in the fold, may contribute to catalysis in many enzymes.

Suggested Citation

  • Katherine A. Henzler-Wildman & Vu Thai & Ming Lei & Maria Ott & Magnus Wolf-Watz & Tim Fenn & Ed Pozharski & Mark A. Wilson & Gregory A. Petsko & Martin Karplus & Christian G. Hübner & Dorothee Kern, 2007. "Intrinsic motions along an enzymatic reaction trajectory," Nature, Nature, vol. 450(7171), pages 838-844, December.
  • Handle: RePEc:nat:nature:v:450:y:2007:i:7171:d:10.1038_nature06410
    DOI: 10.1038/nature06410
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    Citations

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    Cited by:

    1. Santiago Esteban-Martín & Robert Bryn Fenwick & Jörgen Ådén & Benjamin Cossins & Carlos W Bertoncini & Victor Guallar & Magnus Wolf-Watz & Xavier Salvatella, 2014. "Correlated Inter-Domain Motions in Adenylate Kinase," PLOS Computational Biology, Public Library of Science, vol. 10(7), pages 1-7, July.
    2. Nicolas Palopoli & Alexander Miguel Monzon & Gustavo Parisi & Maria Silvina Fornasari, 2016. "Addressing the Role of Conformational Diversity in Protein Structure Prediction," PLOS ONE, Public Library of Science, vol. 11(5), pages 1-14, May.
    3. Gregory D Friedland & Nils-Alexander Lakomek & Christian Griesinger & Jens Meiler & Tanja Kortemme, 2009. "A Correspondence Between Solution-State Dynamics of an Individual Protein and the Sequence and Conformational Diversity of its Family," PLOS Computational Biology, Public Library of Science, vol. 5(5), pages 1-16, May.
    4. Robert Peach & Alexis Arnaudon & Mauricio Barahona, 2022. "Relative, local and global dimension in complex networks," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Kai Wang & Shiyang Long & Pu Tian, 2015. "Hierarchical Conformational Analysis of Native Lysozyme Based on Sub-Millisecond Molecular Dynamics Simulations," PLOS ONE, Public Library of Science, vol. 10(6), pages 1-17, June.
    6. Xiang Zhang & Jingjing Tang & Lingling Wang & Chuan Wang & Lei Chen & Xinqing Chen & Jieshu Qian & Bingcai Pan, 2024. "Nanoconfinement-triggered oligomerization pathway for efficient removal of phenolic pollutants via a Fenton-like reaction," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    7. Sebastian L B König & Mélodie Hadzic & Erica Fiorini & Richard Börner & Danny Kowerko & Wolf U Blanckenhorn & Roland K O Sigel, 2013. "BOBA FRET: Bootstrap-Based Analysis of Single-Molecule FRET Data," PLOS ONE, Public Library of Science, vol. 8(12), pages 1-17, December.
    8. Fabian Paul & Thomas R Weikl, 2016. "How to Distinguish Conformational Selection and Induced Fit Based on Chemical Relaxation Rates," PLOS Computational Biology, Public Library of Science, vol. 12(9), pages 1-17, September.
    9. Dilek Eren & Burak Alakent, 2013. "Frequency Response of a Protein to Local Conformational Perturbations," PLOS Computational Biology, Public Library of Science, vol. 9(9), pages 1-15, September.

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