PXD059316

PXD059316 is an original dataset announced via ProteomeXchange.

Title	Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation
Description	Most sudden cardiac deaths in young people arise from hypertrophic cardiomyopathy, a genetic disease of the heart muscle, with many causative mutations found in the molecular motor beta-cardiac myosin that drives contraction. Therapeutic intervention for hypertrophic cardiomyopathy has until recently been limited to symptomatic relief or invasive procedures. However, small molecule modulators of cardiac myosin are promising therapeutic options to better reduce disease progression. Mavacamten is the first example to gain FDA approval but its molecular mode of action remains unclear, limiting our understanding of its functional effects in disease. To better understand this, we solved the cryoEM structures of beta-cardiac heavy meromyosin in three ADP.Pi-bound states, the primed motor domain in the presence and absence of mavacamten, and the sequestered autoinhibited interacting-heads motif (IHM) in complex with mavacamten. Together with in vitro motility and quantitative crosslinking mass spectrometric analysis, these structures reveal how mavacamten inhibits myosin. For this study we adapted the MS1 label-free quantitation presented by Chen and Rappsiliber. Mavacamten stabilises ADP.Pi binding, stalling the motor domain in a primed state, reducing motor dynamics required for actin-binding cleft closure, and slowing progression through the force generation cycle. Within the two-headed myosin molecule, these effects are propagated and lead to stabilisation of the IHM, through increased contacts at the motor-motor interface.
HostingRepository	PRIDE
AnnounceDate	2026-03-26
AnnouncementXML	Submission_2026-03-26_09:40:29.818.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jaime Pitts
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	crosslinked residues; phosphorylated residue; N6; acetylated residue; iodoacetic acid derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-12-30 15:59:21	ID requested
⏵ 1	2026-03-26 09:40:30	announced

Dataset with its publication pending

submitter keyword: DSBU, skyline,Cardiac myosin, quantitative crosslinking MS

Charlotte Scarf
contact affiliation	Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, Faculty of Medicine and Health, University of Leeds, UK
contact email	c.a.scarff@leeds.ac.uk
lab head
Jaime Pitts
contact affiliation	Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, Faculty of Medicine and Health, University of Leeds, UK
contact email	medjrtp@leeds.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD059316
     1. Label: PRIDE project
     2. Name: Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation