8ACT

structure of the human beta-cardiac myosin folded-back off state

Summary for 8ACT

• Entry DOI: 10.2210/pdb8act/pdb
• EMDB information: 15353
• Descriptor: Myosin-7, Myosin light chain 3, Myosin regulatory light chain 2, ventricular/cardiac muscle isoform, ... (6 entities in total)
• Functional Keywords: cardiac myosin, myosin, human, folded-back off state, contractile protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 277479.21

Authors

Grinzato, A.,Kandiah, E.,Robert-Paganin, J.,Auguin, D.,Kikuti, C.,Nandwani, N.,Moussaoui, D.,Pathak, D.,Ruppel, K.M.,Spudich, J.A.,Houdusse, A. (deposition date: 2022-07-06, release date: 2023-06-07, Last modification date: 2025-07-09)

Primary citation

Grinzato, A.,Auguin, D.,Kikuti, C.,Nandwani, N.,Moussaoui, D.,Pathak, D.,Kandiah, E.,Ruppel, K.M.,Spudich, J.A.,Houdusse, A.,Robert-Paganin, J.
Cryo-EM structure of the folded-back state of human beta-cardiac myosin.
Nat Commun, 14:3166-3166, 2023

PubMed 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' 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.

PubMed: 37258552
DOI: 10.1038/s41467-023-38698-w

Experimental method

ELECTRON MICROSCOPY (3.6 Å)