9YP9

Cryo-EM structure of human beta-cardiac myosin bound to mavacamten in the interacting-heads motif and S2-FH docked state

Summary for 9YP9

• Entry DOI: 10.2210/pdb9yp9/pdb
• EMDB information: 73288
• Descriptor: Myosin-7,General control transcription factor GCN4,Enhanced Green fluorescent protein, Myosin light chain 1/3, skeletal muscle isoform, Myosin regulatory light chain 11, ... (6 entities in total)
• Functional Keywords: cardiac myosin, interacting heads motif, mavacamten, actin binding, contractile protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 382101.87

Authors

Somavarapu, A.K.,Ge, J.,Yengo, C.M.,Craig, R.,Padron, R. (deposition date: 2025-10-13, release date: 2026-04-08, Last modification date: 2026-05-20)

Primary citation

Somavarapu, A.K.,Ge, J.,Yengo, C.M.,Craig, R.,Padron, R.
Cryo-EM reveals how cardiomyopathy therapeutic drugs modulate the myosin motors of the heart.
Sci Adv, 12:eaed6472-eaed6472, 2026

PubMed Abstract: Genetic mutations in myosin, the motor protein that powers the heartbeat, are linked to inherited hypertrophic and dilated cardiomyopathies. Mavacamten and omecamtiv mecarbil are therapeutic, myosin-targeted drugs designed to treat these myopathies, but their mechanism of action has remained unclear. Using single-particle cryo-EM, we determined near-atomic resolution structures of wild-type, mavacamten-bound, and omecamtiv mecarbil-bound myosin molecules. Across all conditions, we observe two distinct, alternate conformations of myosin, not previously reported. We show how mavacamten stabilizes one conformation by reinforcing key electrostatic interfaces in the molecule, whereas omecamtiv mecarbil weakens these interfaces, favoring the second structure. This remodeling elucidates previously unclear allosteric mechanisms through which these drugs either inhibit or enhance myosin activity, countering the deleterious impacts of disease. These findings reveal how drugs modulate myosin structure to control cardiac contractility.

PubMed: 42054467
DOI: 10.1126/sciadv.aed6472

Experimental method

ELECTRON MICROSCOPY (3 Å)