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Intrinsic motions along an enzymatic reaction trajectory

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 environ... Full description

Journal Title: Nature (London) 2007, Vol.450 (7171), p.838-844
Main Author: HENZLER-WILDMAN, Katherine A
Other Authors: THAI, Vu , HÜBNER, Christian G , KERN, Dorothee , MING LEI , OTT, Maria , WOLF-WATZ, Magnus , FENN, Tim , POZHARSKI, Ed , WILSON, Mark A , PETSKO, Gregory A , KARPLUS, Martin
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: Nature Publishing
ID: ISSN: 0028-0836
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recordid: cdi_proquest_miscellaneous_69044795
title: Intrinsic motions along an enzymatic reaction trajectory
format: Article
creator:
  • HENZLER-WILDMAN, Katherine A
  • THAI, Vu
  • HÜBNER, Christian G
  • KERN, Dorothee
  • MING LEI
  • OTT, Maria
  • WOLF-WATZ, Magnus
  • FENN, Tim
  • POZHARSKI, Ed
  • WILSON, Mark A
  • PETSKO, Gregory A
  • KARPLUS, Martin
subjects:
  • ACCELERATION
  • Adenylate Kinase - chemistry
  • Adenylate Kinase - metabolism
  • Analytical, structural and metabolic biochemistry
  • Bacteria - enzymology
  • BASIC BIOLOGICAL SCIENCES
  • BIOCHEMISTRY
  • Biological and medical sciences
  • CATALYSIS
  • CHEMISTRY
  • Computer Simulation
  • CONFIGURATION
  • CONFORMATIONAL CHANGES
  • Crystallography, X-Ray
  • ENERGY TRANSFER
  • ENZYMES
  • Enzymes and enzyme inhibitors
  • FLUORESCENCE
  • Fluorescence Resonance Energy Transfer
  • Fundamental and applied biological sciences. Psychology
  • GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
  • General aspects, investigation methods
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Motion
  • Movement
  • national synchrotron light source
  • NUCLEAR MAGNETIC RESONANCE
  • PHOSPHOTRANSFERASES
  • Protein Conformation
  • RESONANCE
  • SAMPLING
  • Solutions
  • SPECIFICITY
  • Substrate Specificity
  • SUBSTRATES
  • Time Factors
ispartof: Nature (London), 2007, Vol.450 (7171), p.838-844
description: 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.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
url: Link


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titleIntrinsic motions along an enzymatic reaction trajectory
creatorHENZLER-WILDMAN, Katherine A ; THAI, Vu ; HÜBNER, Christian G ; KERN, Dorothee ; MING LEI ; OTT, Maria ; WOLF-WATZ, Magnus ; FENN, Tim ; POZHARSKI, Ed ; WILSON, Mark A ; PETSKO, Gregory A ; KARPLUS, Martin
creatorcontribHENZLER-WILDMAN, Katherine A ; THAI, Vu ; HÜBNER, Christian G ; KERN, Dorothee ; MING LEI ; OTT, Maria ; WOLF-WATZ, Magnus ; FENN, Tim ; POZHARSKI, Ed ; WILSON, Mark A ; PETSKO, Gregory A ; KARPLUS, Martin ; Brookhaven National Laboratory (BNL) National Synchrotron Light Source
descriptionThe 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.
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subjectACCELERATION ; Adenylate Kinase - chemistry ; Adenylate Kinase - metabolism ; Analytical, structural and metabolic biochemistry ; Bacteria - enzymology ; BASIC BIOLOGICAL SCIENCES ; BIOCHEMISTRY ; Biological and medical sciences ; CATALYSIS ; CHEMISTRY ; Computer Simulation ; CONFIGURATION ; CONFORMATIONAL CHANGES ; Crystallography, X-Ray ; ENERGY TRANSFER ; ENZYMES ; Enzymes and enzyme inhibitors ; FLUORESCENCE ; Fluorescence Resonance Energy Transfer ; Fundamental and applied biological sciences. Psychology ; GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE ; General aspects, investigation methods ; Kinetics ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Motion ; Movement ; national synchrotron light source ; NUCLEAR MAGNETIC RESONANCE ; PHOSPHOTRANSFERASES ; Protein Conformation ; RESONANCE ; SAMPLING ; Solutions ; SPECIFICITY ; Substrate Specificity ; SUBSTRATES ; Time Factors
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7FENN, Tim
8POZHARSKI, Ed
9WILSON, Mark A
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descriptionThe 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.
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2Adenylate Kinase - metabolism
3Analytical, structural and metabolic biochemistry
4Bacteria - enzymology
5BASIC BIOLOGICAL SCIENCES
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7Biological and medical sciences
8CATALYSIS
9CHEMISTRY
10Computer Simulation
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12CONFORMATIONAL CHANGES
13Crystallography, X-Ray
14ENERGY TRANSFER
15ENZYMES
16Enzymes and enzyme inhibitors
17FLUORESCENCE
18Fluorescence Resonance Energy Transfer
19Fundamental and applied biological sciences. Psychology
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22Kinetics
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24Models, Molecular
25Motion
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27national synchrotron light source
28NUCLEAR MAGNETIC RESONANCE
29PHOSPHOTRANSFERASES
30Protein Conformation
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32SAMPLING
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37Time Factors
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authorHENZLER-WILDMAN, Katherine A ; THAI, Vu ; HÜBNER, Christian G ; KERN, Dorothee ; MING LEI ; OTT, Maria ; WOLF-WATZ, Magnus ; FENN, Tim ; POZHARSKI, Ed ; WILSON, Mark A ; PETSKO, Gregory A ; KARPLUS, Martin
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4Bacteria - enzymology
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6BIOCHEMISTRY
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17FLUORESCENCE
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19Fundamental and applied biological sciences. Psychology
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33Solutions
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abstractThe 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.
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pmid18026086
doi10.1038/nature06410
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