9GZ3

Beta-cardiac heavy meromyosin motor domain in the primed state

Summary for 9GZ3

• Entry DOI: 10.2210/pdb9gz3/pdb
• EMDB information: 51721
• Descriptor: Myosin-7, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: mavacamten, inhibitor, primed myosin, motor protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 132398.96

Authors

McMillan, S.N.,Pitts, J.R.T.,Barua, B.,Winkelmann, D.A.,Scarff, C.A. (deposition date: 2024-10-03, release date: 2025-03-12)

Primary citation

McMillan, S.N.,Pitts, J.R.T.,Barua, B.,Winkelmann, D.A.,Scarff, C.A.
Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation.
Biorxiv, 2025

PubMed Abstract: 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 has until recently been limited to symptomatic relief or invasive procedures. However, small molecule modulators of cardiac myosin are promising therapeutic options to target 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, to 2.9 Å, 3.4 Å and 3.7 Å global resolution respectively. Together with quantitative crosslinking mass spectrometric analysis, these structures reveal how mavacamten inhibits myosin. 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. Critically, while mavacamten treatment can thus rescue cardiac muscle relaxation in diastole, it can also reduce contractile output in systole in the heart.

PubMed: 39990378
DOI: 10.1101/2025.02.12.637875

Experimental method

ELECTRON MICROSCOPY (3.4 Å)