Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin's prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin's ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin's mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.

Original languageEnglish (US)
Pages (from-to)E1796-E1804
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number10
DOIs
StatePublished - Mar 7 2017

Bibliographical note

Funding Information:
We thank John Lipscomb for use of his sequential stopped-flow instrument. We thank Anne Houdusse for generous communications, Josh Baker and Travis Steward for sharing their cardiac myosin purification procedure (which we modified for the experiments presented here), and Piyali Guhathakurta for expert assistance in the purification of the cardiac myosin used in this work. This study was supported by grants from the American Heart Association (14SDG20480032 to J.M.M.) and from NIH (R01AR32961 and R42DA037622 to D.D.T.). J.A.R. was supported by a Graduate Excellence Fellowship from the University of Minnesota.

Publisher Copyright:
© 2017, National Academy of Sciences. All rights reserved.

Keywords

  • FRET
  • Heart failure
  • Myosin
  • Omecamtiv mecarbil
  • Phosphate release

Fingerprint Dive into the research topics of 'Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke'. Together they form a unique fingerprint.

Cite this