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- EMDB-51719: Beta-cardiac myosin interacting heads motif complexed to mavacamten -

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Basic information

Entry
Database: EMDB / ID: EMD-51719
TitleBeta-cardiac myosin interacting heads motif complexed to mavacamten
Map data
Sample
  • Complex: Beta-cardiac myosin interacting heads motif complexed to mavacamten
    • Protein or peptide: Myosin-7
    • Protein or peptide: Myosin light chain 1/3, skeletal muscle isoform
    • Protein or peptide: Myosin regulatory light chain 11
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHATE ION
  • Ligand: 6-[[(1~{S})-1-phenylethyl]amino]-3-propan-2-yl-1~{H}-pyrimidine-2,4-dione
KeywordsMavacamten / Inhibitor / Interacting heads motif / myosin / MOTOR PROTEIN
Function / homology
Function and homology information


regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / Striated Muscle Contraction / Smooth Muscle Contraction / muscle myosin complex / 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 ...regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / Striated Muscle Contraction / Smooth Muscle Contraction / muscle myosin complex / 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 / muscle filament sliding / myosin complex / myosin II complex / structural constituent of muscle / ventricular cardiac muscle tissue morphogenesis / microfilament motor activity / myofibril / skeletal muscle contraction / striated muscle contraction / ATP metabolic process / skeletal muscle tissue development / stress fiber / cardiac muscle contraction / muscle contraction / regulation of heart rate / sarcomere / Z disc / actin filament binding / calmodulin binding / immune response / calcium ion binding / ATP binding / cytoplasm
Similarity search - Function
: / EF-hand 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. ...: / EF-hand 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 / : / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Myosin light chain 1/3, skeletal muscle isoform / Myosin-7 / Myosin regulatory light chain 11
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsMcMillan SN / Pitts JRT / Barua B / Winkelmann DA / Scarff CA
Funding support United Kingdom, 1 items
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, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_51719.png

Downloads & links

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Map

FileDownload / File: emd_51719.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 360 pix.
= 295.92 Å		0.82 Å/pix.
x 360 pix.
= 295.92 Å		0.82 Å/pix.
x 360 pix.
= 295.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.822 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.119906195 - 2.288657
Average (Standard dev.)0.0016529321 (±0.027170463)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 295.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_51719_msk_1.map
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Additional map: #1

Fileemd_51719_additional_1.map
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Additional map: #2

Fileemd_51719_additional_2.map
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Half map: #1

Fileemd_51719_half_map_1.map
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Half map: #2

Fileemd_51719_half_map_2.map
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Sample components

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Entire : Beta-cardiac myosin interacting heads motif complexed to mavacamten

EntireName: Beta-cardiac myosin interacting heads motif complexed to mavacamten
Components
  • Complex: Beta-cardiac myosin interacting heads motif complexed to mavacamten
    • Protein or peptide: Myosin-7
    • Protein or peptide: Myosin light chain 1/3, skeletal muscle isoform
    • Protein or peptide: Myosin regulatory light chain 11
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHATE ION
  • Ligand: 6-[[(1~{S})-1-phenylethyl]amino]-3-propan-2-yl-1~{H}-pyrimidine-2,4-dione

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Supramolecule #1: Beta-cardiac myosin interacting heads motif complexed to mavacamten

SupramoleculeName: Beta-cardiac myosin interacting heads motif complexed to mavacamten
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: Complex crosslinked with bis(sulfosuccinimidyl)suberate (BS3)
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Myosin-7

MacromoleculeName: Myosin-7 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 131.852484 KDa
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: GDSEMAVFGA AAPYLRKSEK ERLEAQTRPF DLKKDVFVPD DKQEFVKAKI VSREGGKVTA ETEYGKTVTV KEDQVMQQNP PKFDKIEDM AMLTFLHEPA VLYNLKDRYG SWMIYTYSGL FCVTVNPYKW LPVYTPEVVA AYRGKKRSEA PPHIFSISDN A YQYMLTDR ...String:
GDSEMAVFGA AAPYLRKSEK ERLEAQTRPF DLKKDVFVPD DKQEFVKAKI VSREGGKVTA ETEYGKTVTV KEDQVMQQNP PKFDKIEDM AMLTFLHEPA VLYNLKDRYG SWMIYTYSGL FCVTVNPYKW LPVYTPEVVA AYRGKKRSEA PPHIFSISDN A YQYMLTDR ENQSILITGE SGAGKTVNTK RVIQYFAVIA AIGDRSKKDQ SPGKGTLEDQ IIQANPALEA FGNAKTVRND NS SRFGKFI RIHFGATGKL ASADIETYLL EKSRVIFQLK AERDYHIFYQ ILSNKKPELL DMLLITNNPY DYAFISQGET TVA SIDDAE ELMATDNAFD VLGFTSEEKN SMYKLTGAIM HFGNMKFKLK QREEQAEPDG TEEADKSAYL MGLNSADLLK GLCH PRVKV GNEYVTKGQN VQQVIYATGA LAKAVYERMF NWMVTRINAT LETKQPRQYF IGVLDIAGFE IFDFNSFEQL CINFT NEKL QQFFNHHMFV LEQEEYKKEG IEWTFIDFGM DLQACIDLIE KPMGIMSILE EECMFPKATD MTFKAKLFDN HLGKSA NFQ KPRNIKGKPE AHFSLIHYAG IVDYNIIGWL QKNKDPLNET VVGLYQKSSL KLLSTLFANY AGADAPIEKG KGKAKKG SS FQTVSALHRE NLNKLMTNLR STHPHFVRCI IPNETKSPGV MDNPLVMHQL RCNGVLEGIR ICRKGFPNRI LYGDFRQR Y RILNPAAIPE GQFIDSRKGA EKLLSSLDID HNQYKFGHTK VFFKAGLLGL LEEMRDERLS RIITRIQAQS RGVLARMEY KKLLERRDSL LVIQWNIRAF MGVKNWPWMK LYFKIKPLLK SAEREKEMAS MKEEFTRLKE ALEKSEARRK ELEEKMVSLL QEKNDLQLQ VQAEQDNLAD AEERCDQLIK NKIQLEAKVK EMNERLEDEE EMNAELTAKK RKLEDECSEL KRDIDDLELT L AKVEKEKH ATENKVKNLT EEMAGLDEII AKLTKEKKAL QEAHQQALDD LQAEEDKVNT LTKAKVKLEQ QVDDLEGSLE QE KKVRMDL ERAKRKLEGD LKLTQESIMD LENDKQQLDE RLKKKDFELN ALNARIEDEQ ALGSQLQKKL KELQARIEEL EEE LESERT ARAKVEKLRS DDYKDDDDK

UniProtKB: Myosin-7

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Macromolecule #2: Myosin light chain 1/3, skeletal muscle isoform

MacromoleculeName: Myosin light chain 1/3, skeletal muscle isoform / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 20.489297 KDa
SequenceString:
APKKDVKKPA AAPAPAPAPA PAPAKPKEEK IDLSAIKIEF SKEQQEDFKE AFLLFDRTGE CKITLSQVGD VLRALGTNPT NAEVKKVLG NPSNEEMNAK KIEFEQFLPM MQAISNNKDQ GGYEDFVEGL RVFDKEGNGT VMGAELRHVL ATLGEKMKEE E VEALLAGQ EDSNGCINYE AFVKHIMSV

UniProtKB: Myosin light chain 1/3, skeletal muscle isoform

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Macromolecule #3: Myosin regulatory light chain 11

MacromoleculeName: Myosin regulatory light chain 11 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 18.847246 KDa
SequenceString:
APKKAKRRAG AEGSSNVFSM FDQTQIQEFK EAFTVIDQNR DGIIDKEDLR DTFAAMGRLN VKNEELDAMM KEASGPINFT VFLTMFGEK LKGADPEDVI TGAFKVLDPE GKGTIKKQFL EELLTTQCDR FSQEEIKNMW AAFPPDVGGN VDYKNICYVI T HGDAKDQE

UniProtKB: Myosin regulatory light chain 11

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 2 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Macromolecule #6: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION

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Macromolecule #7: 6-[[(1~{S})-1-phenylethyl]amino]-3-propan-2-yl-1~{H}-pyrimidine-2...

MacromoleculeName: 6-[[(1~{S})-1-phenylethyl]amino]-3-propan-2-yl-1~{H}-pyrimidine-2,4-dione
type: ligand / ID: 7 / Number of copies: 2 / Formula: XB2
Molecular weightTheoretical: 273.33 Da
Chemical component information

ChemComp-XB2:
6-[[(1~{S})-1-phenylethyl]amino]-3-propan-2-yl-1~{H}-pyrimidine-2,4-dione

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.34 mg/mL
BufferpH: 7.2
Component:
ConcentrationFormulaName
50.0 mMKClPotassium chloride
10.0 mMMOPS3-(N-morpholino)propanesulfonic acid
2.0 mMMgCl2Magnesium chloride
1.0 mMATPAdenosine triphosphate
1.0 mMEGTAegtazic acid
2.5 %DMSODimethylsulfoxide
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV
DetailsComplexed to mavacamten and crosslinked with bis(sulfosuccinimidyl)suberate (BS3)

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 2 / Number real images: 34287 / Average exposure time: 3.8 sec. / Average electron dose: 43.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.5 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3876170
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 197869
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6z47


Chain - Source name: Modeller / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9gz1:
Beta-cardiac myosin interacting heads motif complexed to mavacamten

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