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- PDB-9gz3: Beta-cardiac heavy meromyosin motor domain in the primed state -

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Basic information

Entry
Database: PDB / ID: 9gz3
TitleBeta-cardiac heavy meromyosin motor domain in the primed state
ComponentsMyosin-7
KeywordsMOTOR PROTEIN / Mavacamten / Inhibitor / Primed myosin
Function / homology
Function and homology information


regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / muscle myosin complex / muscle filament sliding / regulation of the force of heart contraction / transition between fast and slow fiber / myosin filament / adult heart development / cardiac muscle hypertrophy in response to stress / myosin II complex ...regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / muscle myosin complex / muscle filament sliding / regulation of the force of heart contraction / transition between fast and slow fiber / myosin filament / adult heart development / cardiac muscle hypertrophy in response to stress / myosin II complex / myosin complex / ventricular cardiac muscle tissue morphogenesis / sarcomere organization / microfilament motor activity / myofibril / skeletal muscle contraction / ATP metabolic process / striated muscle contraction / stress fiber / cardiac muscle contraction / muscle contraction / regulation of heart rate / sarcomere / Z disc / actin filament binding / calmodulin binding / ATP binding / cytoplasm
Similarity search - Function
DNA repair protein XRCC4-like, C-terminal / Myosin tail / Myosin tail / Myosin N-terminal SH3-like domain / Myosin S1 fragment, N-terminal / Myosin, N-terminal, SH3-like / Myosin N-terminal SH3-like domain profile. / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site / Myosin head, motor domain ...DNA repair protein XRCC4-like, C-terminal / Myosin tail / Myosin tail / Myosin N-terminal SH3-like domain / Myosin S1 fragment, N-terminal / Myosin, N-terminal, SH3-like / Myosin N-terminal SH3-like domain profile. / Short calmodulin-binding motif containing conserved Ile and Gln residues. / IQ motif, EF-hand binding site / Myosin head, motor domain / Myosin head (motor domain) / Myosin motor domain profile. / Myosin. Large ATPases. / IQ motif profile. / Kinesin motor domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / PHOSPHATE ION / Myosin-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsMcMillan, S.N. / Pitts, J.R.T. / Barua, B. / Winkelmann, D.A. / Scarff, C.A.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
British Heart Foundation United Kingdom
CitationJournal: bioRxiv / Year: 2025
Title: Mavacamten inhibits myosin activity by stabilising the myosin interacting-heads motif and stalling motor force generation.
Authors: Sean N McMillan / Jaime R T Pitts / Bipasha Barua / Donald A Winkelmann / Charlotte A Scarff /
Abstract: 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 ...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 Å, 3.4 Å and 3.7 Å 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.
History
DepositionOct 3, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Mar 12, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Myosin-7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,3994
Polymers131,8521
Non-polymers5463
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Myosin-7 / Myosin heavy chain 7 / Myosin heavy chain slow isoform / MyHC-slow / Myosin heavy chain / cardiac ...Myosin heavy chain 7 / Myosin heavy chain slow isoform / MyHC-slow / Myosin heavy chain / cardiac muscle beta isoform / MyHC-beta


Mass: 131852.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYH7, MYHCB / Production host: Mus musculus (house mouse) / References: UniProt: P12883
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Beta-cardiac heavy meromyosin in the primed state / Type: COMPLEX
Details: Complex crosslinked with bis(sulfosuccinimidyl)suberate (BS3)
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Mus musculus (house mouse)
Buffer solutionpH: 7.2
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMPotassium chlorideKCl1
210 mM3-(N-morpholino)propanesulfonic acidMOPS1
32 mMMagnesium chlorideMgCl21
41 mMAdenosine triphosphateATP1
51 mMegtazic acidEGTA1
62.5 %DimethylsulfoxideDMSO1
SpecimenConc.: 0.34 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Crosslinked with bis(sulfosuccinimidyl)suberate (BS3)
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Alignment procedure: COMA FREE
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 3.6 sec. / Electron dose: 42.9 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 9948

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Processing

EM software
IDNameCategory
1Topazparticle selection
2EPUimage acquisition
4CTFFINDCTF correction
7ISOLDEmodel fitting
8Cootmodel fitting
10PHENIXmodel refinement
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
13cryoSPARCclassification
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3436065
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88809 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingAccession code: 6Z47 / Source name: Modeller / Type: in silico model

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