9gz1

Beta-cardiac myosin interacting heads motif complexed to mavacamten

spinqualitylabelsall models 9gz1, resolution 3.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9gz1 is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.7Å Ligands: ADP, MG, PO4, XB2 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 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 A, 3.4 A and 3.7 A 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. Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation.,McMillan SN, Pitts JRT, Barua B, Winkelmann DA, Scarff CA bioRxiv [Preprint]. 2025 Feb 17:2025.02.12.637875. doi: , 10.1101/2025.02.12.637875. PMID:39990378 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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