A small-molecule inhibitor of skeletal muscle myosin II.
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, monastrol, suggests that motor proteins may be potential targets for therapeutic applications.
Cheung
A
A
Institute for Chemistry and Cell Biology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.
Dantzig
J A
JA
Hollingworth
S
S
Baylor
S M
SM
Goldman
Y E
YE
Mitchison
T J
TJ
Straight
A F
AF
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D020409:Molecular Motor Proteins / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D015879:Myosin Subfragments / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019151:Peptide Library; D011817:Rabbits; D011898:Ranidae; D051381:Rats; D024744:Skeletal Muscle Myosins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D020409:Molecular Motor Proteins; D015879:Myosin Subfragments; C444880:N-benzyl-p-toluene sulfonamide; D019151:Peptide Library; D013449:Sulfonamides; D014050:Toluene; D000251:Adenosine Triphosphatases; D024744:Skeletal Muscle Myosins; D002118:Calcium