8act | pdb_00008act

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

spinqualitylabelsall models 8act, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8act is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ADP, M3L, MG, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MYH7_HUMAN Defects in MYH7 are the cause of familial hypertrophic cardiomyopathy type 1 (CMH1) [MIM:192600. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. Defects in MYH7 are the cause of myopathy myosin storage (MYOMS) [MIM:608358. In this disorder, muscle biopsy shows type 1 fiber predominance and increased interstitial fat and connective tissue. Inclusion bodies consisting of the beta cardiac myosin heavy chain are present in the majority of type 1 fibers, but not in type 2 fibers. Defects in MYH7 are the cause of scapuloperoneal myopathy MYH7-related (SPMM) [MIM:181430; also known as scapuloperoneal syndrome myopathic type. SPMM is a progressive muscular atrophia beginning in the lower legs and affecting the shoulder region earlier and more severely than distal arm. Defects in MYH7 are a cause of cardiomyopathy dilated type 1S (CMD1S) [MIM:613426. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Defects in MYH7 are the cause of myopathy distal type 1 (MPD1) [MIM:160500. MPD1 is a muscular disorder characterized by early-onset selective weakness of the great toe and ankle dorsiflexors, followed by weakness of the finger extensors. Mild proximal weakness occasionally develops years later after the onset of the disease. Function MYH7_HUMAN Muscle contraction. Publication Abstract from PubMed 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 beta-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 A 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. Cryo-EM structure of the folded-back state of human beta-cardiac myosin.,Grinzato A, Auguin D, Kikuti C, Nandwani N, Moussaoui D, Pathak D, Kandiah E, Ruppel KM, Spudich JA, Houdusse A, Robert-Paganin J Nat Commun. 2023 May 31;14(1):3166. doi: 10.1038/s41467-023-38698-w. PMID:37258552 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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