National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
NIH-RM1GM131981-01
米国
Agence Nationale de la Recherche (ANR)
ANR-21-CE11-0022-01
フランス
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
NIH-R01GM33289
米国
引用
ジャーナル: Nat Commun / 年: 2023 タイトル: Cryo-EM structure of the folded-back state of human β-cardiac myosin. 著者: 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 / 要旨: 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.
モデルのタイプ: OTHER 詳細: 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 ...詳細: 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).
最終 再構成
解像度のタイプ: BY AUTHOR / 解像度: 3.2 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 213596