Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin

Proceedings of the National Academy of Sciences of the United States of America
John A RohdeJoseph M Muretta

Abstract

We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and a prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin not found in the single-headed S1 myosin motor fragment. We determined this by measuring cardiac myosin actin-activated and actin-independent ATPase and single-ATP turnover kinetics. A two-headed myosin fragment exhibits distinct autoinhibited ATP turnover kinetics compared with a single-headed fragment. Mavacamten enhanced this autoinhibition. It also enhanced autoinhibition of ADP release. Furthermore, actin changes the structure of the autoinhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state.

References

Jan 7, 1997·Proceedings of the National Academy of Sciences of the United States of America·K M TrybusH L Sweeney
May 16, 2000·The Journal of Biological Chemistry·P A EllisonC R Cremo
Aug 27, 2005·Nature·John L WoodheadRaúl Padrón
Mar 28, 2006·Current Opinion in Structural Biology·Roger Craig, John L Woodhead
Aug 21, 2007·Journal of Molecular Biology·Stan A BurgessPeter J Knight
Jan 24, 2008·The Journal of Biological Chemistry·Máté GyimesiAndrás Málnási-Csizmadia
Feb 7, 2008·Proceedings of the National Academy of Sciences of the United States of America·Maria E ZoghbiRoger Craig
May 23, 2008·Molecular Biology of the Cell·Hyun Suk JungRoger Craig
Mar 18, 2009·Methods in Enzymology·Enrique M De La Cruz, E Michael Ostap
Dec 8, 2009·Proceedings of the National Academy of Sciences of the United States of America·Melanie A StewartRoger Cooke
Apr 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Massimo ReconditiMalcolm Irving
Jul 19, 2011·Journal of Molecular Biology·Nariman NaberEdward Pate
Dec 20, 2012·Proceedings of the National Academy of Sciences of the United States of America·Hind A Al-KhayatEdward P Morris
May 8, 2013·Proceedings of the National Academy of Sciences of the United States of America·John L WoodheadRoger Craig
Dec 18, 2013·The Journal of Physiology·Massimo ReconditiGabriella Piazzesi
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·John A RohdeJoseph M Muretta
May 10, 2017·Nature Structural & Molecular Biology·Suman NagJames A Spudich
Jul 19, 2017·Biophysics Reviews·Darshan V TrivediJames A Spudich
Aug 16, 2017·The Journal of Biological Chemistry·Raja F KawasHector M Rodriguez
Feb 16, 2018·Proceedings of the National Academy of Sciences of the United States of America·Kyoung Hwan LeeRoger Craig
Feb 17, 2018·Journal of Molecular and Cellular Cardiology·Thomas KampourakisMalcolm Irving
Aug 15, 2018·Proceedings of the National Academy of Sciences of the United States of America·Robert L AndersonJames A Spudich

❮ Previous
Next ❯

Citations

Feb 16, 2019·Pflügers Archiv : European journal of physiology·James A Spudich
Feb 23, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Alexander J SparrowPaul Robinson
Feb 19, 2020·Expert Opinion on Drug Discovery·Joshua B HolmesJulian E Stelzer
Mar 15, 2020·Annual Review of Biochemistry·Darshan V TrivediJames A Spudich
Nov 20, 2019·International Journal of Molecular Sciences·John Squire
Aug 15, 2018·Proceedings of the National Academy of Sciences of the United States of America·Robert L AndersonJames A Spudich
Feb 12, 2019·Pflügers Archiv : European journal of physiology·Theresia Kraft, Judith Montag
May 31, 2019·Proceedings of the National Academy of Sciences of the United States of America·James W McNamaraSakthivel Sadayappan
Oct 30, 2018·Journal of the American Heart Association·Ranganath MamidiJulian E Stelzer
Jan 8, 2020·International Journal of Molecular Sciences·Osamu Tsukamoto
Mar 21, 2019·The Journal of General Physiology·Richard L Moss, R John Solaro
Dec 19, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Peter O AwindaBertrand C W Tanner
Jan 13, 2021·Current Cardiology Reports·Fergus StaffordJodie Ingles
Jan 30, 2021·The Journal of General Physiology·Michael J Greenberg, Jil C Tardiff
Feb 11, 2021·ELife·Suman Nag, Darshan V Trivedi
Dec 20, 2020·International Journal of Molecular Sciences·Khulud Alsulami, Steven Marston
Sep 23, 2020·British Journal of Pharmacology·Peter O AwindaBertrand C W Tanner
Feb 28, 2021·The Journal of Biological Chemistry·Osha Roopnarine, David D Thomas
Jun 10, 2020·Biochemical and Biophysical Research Communications·Daniil V ShchepkinGalina V Kopylova
Apr 15, 2021·Proceedings of the National Academy of Sciences of the United States of America·So-Jin Park-HolohanLuca Fusi
Apr 24, 2021·The Journal of General Physiology·Beatrice ScelliniChiara Tesi
Apr 18, 2021·Biophysical Journal·Wanjian TangChristopher M Yengo
May 22, 2021·Circulation Research·Yiangos PsarasChristopher N Toepfer
May 30, 2020·Journal of the American College of Cardiology·Jane E Wilcox, Elizabeth M McNally
Jun 13, 2021·Proceedings of the National Academy of Sciences of the United States of America·Alison Schroer Vander RoestDaniel Bernstein
Nov 7, 2019·Chemical Reviews·Julien Robert-PaganinAnne Houdusse
Sep 6, 2021·The Journal of Biological Chemistry·Sami ChuDavid D Thomas
Dec 11, 2021·The Journal of General Physiology·Roger Craig, Raúl Padrón

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.