National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
NIH-RM1GM131981-01
United States
Agence Nationale de la Recherche (ANR)
ANR-21-CE11-0022-01
France
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
NIH-R01GM33289
United States
Citation
Journal: Nat Commun / Year: 2023 Title: Cryo-EM structure of the folded-back state of human β-cardiac myosin. Authors: Alessandro Grinzato / Daniel Auguin / Carlos Kikuti / Neha Nandwani / Dihia Moussaoui / Divya Pathak / Eaazhisai Kandiah / Kathleen M Ruppel / James A Spudich / Anne Houdusse / Julien Robert-Paganin / Abstract: To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' ...To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 Å resolution, providing details of all the interfaces stabilizing the 'off' state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the 'off' state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability.
Type of model: OTHER Details: The coiled-coil S2 region was fitted from the crystal structure (Blankenfeldt et al., 2006; PDB code 2FXM). The IQ2/RLC region was obtained by homology modeling based on the SmMyo2 IHM ...Details: The coiled-coil S2 region was fitted from the crystal structure (Blankenfeldt et al., 2006; PDB code 2FXM). The IQ2/RLC region was obtained by homology modeling based on the SmMyo2 IHM (Heissler et al., 2021; PDB code 7MF3).
Final reconstruction
Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 213596
Initial angle assignment
Type: MAXIMUM LIKELIHOOD
Final angle assignment
Type: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)
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