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Structure paper

TitleMavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateFeb 17, 2025
AuthorsSean N McMillan / Jaime R T Pitts / Bipasha Barua / Donald A Winkelmann / Charlotte A Scarff /
PubMed AbstractMost 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 ...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.
External linksbioRxiv / PubMed:39990378 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.7 Å
Structure data

51719

9gz1

EMDB-51719, PDB-9gz1:
Beta-cardiac myosin interacting heads motif complexed to mavacamten
Method: EM (single particle) / Resolution: 3.7 Å

51720

9gz2

EMDB-51720, PDB-9gz2:
Beta-cardiac heavy meromyosin motor domain in the primed state complexed to mavacamten
Method: EM (single particle) / Resolution: 2.9 Å

51721

9gz3

EMDB-51721, PDB-9gz3:
Beta-cardiac heavy meromyosin motor domain in the primed state
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-PO4:
PHOSPHATE ION

ChemComp-XB2:
6-[[(1~{S})-1-phenylethyl]amino]-3-propan-2-yl-1~{H}-pyrimidine-2,4-dione / medication, inhibitor*YM

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMOTOR PROTEIN / Mavacamten / Inhibitor / Interacting heads motif / myosin / Primed myosin

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