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A small-molecule inhibitor of skeletal muscle myosin II

Nature Cell Biology volume 4, pages 83–88 (2002)Cite this article

Abstract

We screened a small-molecule library for inhibitors of rabbit muscle myosin II subfragment 1 (S1) actin-stimulated ATPase activity. The best inhibitor, N-benzyl-p-toluene sulphonamide (BTS), an aryl sulphonamide, inhibited the Ca2+-stimulated S1 ATPase, and reversibly blocked gliding motility. Although BTS does not compete for the nucleotide-binding site of myosin, it weakens myosin's interaction with F-actin. BTS reversibly suppressed force production in skinned skeletal muscle fibres from rabbit and frog skin at micromolar concentrations. BTS suppressed twitch production of intact frog fibres with minimum alteration of Ca2+ metabolism. BTS is remarkably specific, as it was much less effective in suppressing contraction in rat myocardial or rabbit slow-twitch muscle, and did not inhibit platelet myosin II. The isolation of BTS and the recently discovered Eg5 kinesin inhibitor, monastrol1, suggests that motor proteins may be potential targets for therapeutic applications.

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Figure 1: Screen for inhibitors of myosin II.
Figure 2: Inhibition of skeletal myosin by BTS.
Figure 3: BTS inhibition of muscle contractile properties.
Figure 4: Plots of tension suppression by BTS for all fibre types tested.

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Acknowledgements

We thank Margot Quinlan and Alex Shaw for the heavy meromyosin used in these studies. We thank George McClellan for supplying the heart muscle preparations. This research was supported by grants from the National Institutes of Health to Y.E.G. (HL15835), S.M.B. (NS17620) and T.J.M. (GM62566, GM23928), and to T.J.M. from Merck & Co. and E. Merck. A.C. was supported by Merck & Co. A.F.S. was supported by the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation.

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Authors and Affiliations

  1. Institute for Chemistry and Cell Biology, Harvard Medical School, 250 Longwood Avenue, Boston, 02115, Massachusetts, USA

    A. Cheung, T. J. Mitchison & A. F. Straight

  2. Department of Physiology and the Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    J. A. Dantzig, S. Hollingworth, S. M. Baylor & Y.E. Goldman

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  1. A. Cheung
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  2. J. A. Dantzig
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Correspondence to A. F. Straight.

Supplementary information

Supplementary figures

Figure S1 Synthesis and characterization of the sulfonamide. (PDF 34 kb)

Figure S2 HMM Sedimentation in the absence of F-actin as described in Fig 2c.

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Cheung, A., Dantzig, J., Hollingworth, S. et al. A small-molecule inhibitor of skeletal muscle myosin II. Nat Cell Biol 4, 83–88 (2002). https://doi.org/10.1038/ncb734

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