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Journal article
Extensive conformational transitions are required to turn on ATP hydrolysis in myosin
Journal of molecular biology, v 381(5), pp 1407-1420
19 Sep 2008
PMID: 18619975
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Conventional myosin is representative of biomolecular motors in which the hydrolysis of adenosine triphosphate (ATP) is coupled to large-scale structural transitions both in and remote from the active site. The mechanism that underlies such "mechanochemical coupling," especially the causal relationship between hydrolysis and allosteric structural changes, has remained elusive despite extensive experimental and computational analyses. In this study, using combined quantum mechanical and molecular mechanical simulations and different conformations of the myosin motor domain, we provide evidence to support that regulation of ATP hydrolysis activity is not limited to residues in the immediate environment of the phosphate. Specifically, we illustrate that efficient hydrolysis of ATP depends not only on the proper orientation of the lytic water but a I so on the structural stability of several nearby residues, especially the Arg238-Glu459 salt bridge (the numbering of residues follows myosin II in Dictyostelium discoideum) and the water molecule that spans this salt bridge and the lytic water. More importantly, by comparing the hydrolysis activities in two motor conformations with very similar active-site (i.e., Switches I and II) configurations, which distinguished this work from our previous study, the results clearly indicate that the ability of these residues to perform crucial electrostatic stabilization relies on the configuration of residues in the nearby N-terminus of the relay helix and the "wedge loop." Without the structural support from those motifs, residues in a closed active site in the post-rigor motor domain undergo subtle structural variations that lead to consistently higher calculated ATP hydrolysis barriers than in the pre-powerstroke state. In other words, starting from the post-rigor state, turning on the ATPase activity requires not only displacement of Switch II to close the active site but also structural transitions in the N-terminus of the relay helix and the "wedge loop," which have been proposed previously to be ultimately coupled to the rotation of the converter subdomain 40 angstrom away. (c) 2008 Elsevier Ltd. All rights reserved.
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Details
- Title
- Extensive conformational transitions are required to turn on ATP hydrolysis in myosin
- Creators
- Yang Yang - Drexel University, ChemistryHaibo Yu - University of Wisconsin–MadisonQiang Cui - University of Wisconsin–Madison
- Publication Details
- Journal of molecular biology, v 381(5), pp 1407-1420
- Publisher
- Elsevier
- Number of pages
- 14
- Grant note
- Sloan Research Fellowship; Alfred P. Sloan Foundation R01GM071428 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01-GM071428 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemistry
- Web of Science ID
- WOS:000259169100025
- Scopus ID
- 2-s2.0-48749103219
- Other Identifier
- 991021874714304721
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- Web of Science research areas
- Biochemistry & Molecular Biology