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- PDB-9yp4: Cryo-EM structure of human beta-cardiac myosin bound to omecamtiv... -

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Basic information

Entry
Database: PDB / ID: 9yp4
TitleCryo-EM structure of human beta-cardiac myosin bound to omecamtiv mecarbil in the interacting-heads motif and S2-FH docked state
Components
  • Myosin light chain 1/3, skeletal muscle isoform
  • Myosin regulatory light chain 11
  • Myosin-7,General control transcription factor GCN4,Enhanced Green fluorescent protein
KeywordsCONTRACTILE PROTEIN / Cardiac Myosin / Interacting Heads Motif / Omecamtiv Mecarbil / Actin Binding
Function / homology
Function and homology information


regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / unconventional myosin complex / Striated Muscle Contraction / contractile muscle fiber / Smooth Muscle Contraction / FCERI mediated MAPK activation / protein localization to nuclear periphery / muscle myosin complex / Activation of the AP-1 family of transcription factors ...regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / unconventional myosin complex / Striated Muscle Contraction / contractile muscle fiber / Smooth Muscle Contraction / FCERI mediated MAPK activation / protein localization to nuclear periphery / muscle myosin complex / Activation of the AP-1 family of transcription factors / negative regulation of ribosomal protein gene transcription by RNA polymerase II / positive regulation of cellular response to amino acid starvation / response to amino acid starvation / mediator complex binding / regulation of the force of heart contraction / transition between fast and slow fiber / myosin filament / Oxidative Stress Induced Senescence / cardiac muscle hypertrophy in response to stress / muscle filament sliding / myosin complex / adult heart development / myosin II complex / structural constituent of muscle / ventricular cardiac muscle tissue morphogenesis / microfilament motor activity / myofibril / amino acid biosynthetic process / cytoskeletal motor activity / TFIID-class transcription factor complex binding / positive regulation of RNA polymerase II transcription preinitiation complex assembly / positive regulation of transcription initiation by RNA polymerase II / skeletal muscle tissue development / ATP metabolic process / striated muscle contraction / skeletal muscle contraction / cardiac muscle contraction / stress fiber / regulation of heart rate / cellular response to nutrient levels / muscle contraction / cellular response to amino acid starvation / bioluminescence / sarcomere / generation of precursor metabolites and energy / RNA polymerase II transcription regulator complex / Z disc / actin filament binding / DNA-binding transcription activator activity, RNA polymerase II-specific / transcription regulator complex / sequence-specific DNA binding / RNA polymerase II-specific DNA-binding transcription factor binding / DNA-binding transcription factor activity, RNA polymerase II-specific / calmodulin binding / intracellular signal transduction / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / calcium ion binding / chromatin binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / ATP binding / identical protein binding / nucleus / cytoplasm
Similarity search - Function
: / EF-hand domain / : / Basic region leucine zipper / DNA repair protein XRCC4-like, C-terminal / Myosin tail / Myosin tail / Myosin N-terminal SH3-like domain / Myosin S1 fragment, N-terminal / Basic-leucine zipper (bZIP) domain signature. ...: / EF-hand domain / : / Basic region leucine zipper / DNA repair protein XRCC4-like, C-terminal / Myosin tail / Myosin tail / Myosin N-terminal SH3-like domain / Myosin S1 fragment, N-terminal / Basic-leucine zipper (bZIP) domain signature. / Basic-leucine zipper (bZIP) domain profile. / basic region leucin zipper / Basic-leucine zipper domain / Basic-leucine zipper domain superfamily / 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 motor domain profile. / Myosin head, motor domain / Myosin head (motor domain) / Myosin. Large ATPases. / IQ motif profile. / Kinesin motor domain superfamily / : / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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
Chem-2OW / ADENOSINE-5'-DIPHOSPHATE / PHOSPHATE ION / General control transcription factor GCN4 / Myosin light chain 1/3, skeletal muscle isoform / Myosin-7 / Green fluorescent protein / Myosin regulatory light chain 11
Similarity search - Component
Biological speciesHomo sapiens (human)
Saccharomyces cerevisiae (brewer's yeast)
Aequorea victoria (jellyfish)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.5 Å
AuthorsSomavarapu, A.K. / Craig, R. / Padron, R.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL164560 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)AR081941 United States
CitationJournal: Sci Adv / Year: 2026
Title: Cryo-EM reveals how cardiomyopathy therapeutic drugs modulate the myosin motors of the heart.
Authors: Arun Kumar Somavarapu / Jinghua Ge / Christopher M Yengo / Roger Craig / Raul Padron /
Abstract: Genetic mutations in myosin, the motor protein that powers the heartbeat, are linked to inherited hypertrophic and dilated cardiomyopathies. Mavacamten and omecamtiv mecarbil are therapeutic, myosin- ...Genetic mutations in myosin, the motor protein that powers the heartbeat, are linked to inherited hypertrophic and dilated cardiomyopathies. Mavacamten and omecamtiv mecarbil are therapeutic, myosin-targeted drugs designed to treat these myopathies, but their mechanism of action has remained unclear. Using single-particle cryo-EM, we determined near-atomic resolution structures of wild-type, mavacamten-bound, and omecamtiv mecarbil-bound myosin molecules. Across all conditions, we observe two distinct, alternate conformations of myosin, not previously reported. We show how mavacamten stabilizes one conformation by reinforcing key electrostatic interfaces in the molecule, whereas omecamtiv mecarbil weakens these interfaces, favoring the second structure. This remodeling elucidates previously unclear allosteric mechanisms through which these drugs either inhibit or enhance myosin activity, countering the deleterious impacts of disease. These findings reveal how drugs modulate myosin structure to control cardiac contractility.
History
DepositionOct 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
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Revision 1.1May 20, 2026Group: Data collection / Database references / Category: citation / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Myosin-7,General control transcription factor GCN4,Enhanced Green fluorescent protein
B: Myosin-7,General control transcription factor GCN4,Enhanced Green fluorescent protein
C: Myosin light chain 1/3, skeletal muscle isoform
D: Myosin light chain 1/3, skeletal muscle isoform
E: Myosin regulatory light chain 11
F: Myosin regulatory light chain 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)382,35812
Polymers380,5116
Non-polymers1,8476
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 6 molecules ABCDEF

#1: Protein Myosin-7,General control transcription factor GCN4,Enhanced Green fluorescent protein / 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 / Amino acid biosynthesis regulatory protein / General control protein GCN4


Mass: 150656.500 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Saccharomyces cerevisiae (brewer's yeast), (gene. exp.) Aequorea victoria (jellyfish)
Gene: MYH7, MYHCB, GCN4, AAS101, AAS3, ARG9, YEL009C, GFP / Production host: Mus musculus (house mouse)
References: UniProt: P12883, UniProt: P03069, UniProt: P42212
#2: Protein Myosin light chain 1/3, skeletal muscle isoform / MLC1/MLC3 / MLC1F/MLC3F / Myosin light chain alkali 1/2 / Myosin light chain A1/A2


Mass: 20620.490 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P05977
#3: Protein Myosin regulatory light chain 11 / Fast skeletal myosin light chain 2 / MLC2F / Myosin light chain 11 / Myosin regulatory light chain ...Fast skeletal myosin light chain 2 / MLC2F / Myosin light chain 11 / Myosin regulatory light chain 2 / skeletal muscle isoform


Mass: 18978.445 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P97457

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Non-polymers , 3 types, 6 molecules

#4: Chemical ChemComp-2OW / methyl 4-(2-fluoro-3-{[(6-methylpyridin-3-yl)carbamoyl]amino}benzyl)piperazine-1-carboxylate / omecamtiv mercarbil


Mass: 401.435 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H24FN5O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Human beta-cardiac myosin bound to omecamtiv mecarbil in the interacting-heads motif and S2-FH docked stateCOMPLEX#1-#30MULTIPLE SOURCES
2Myosin-7COMPLEX#11RECOMBINANT
3Myosin light chain 1/3 and Myosin regulatory light chain 11COMPLEX#2-#31NATURAL
Molecular weightValue: 0.11652168 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
Source (recombinant)Organism: Mus musculus (house mouse)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 49.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategoryFitting-ID
1cryoSPARCparticle selection
2Topazparticle selection
5cryoSPARCCTF correction
8UCSF ChimeraXmodel fitting1
9MDFFmodel fitting1
10Cootmodel fitting1
12cryoSPARCinitial Euler assignment
13cryoSPARCfinal Euler assignment
14cryoSPARCclassification
15cryoSPARC3D reconstruction
16PHENIX1.20.1_4487model refinement1
17PHENIX1.20.1_4487model refinement2
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 19218 / Symmetry type: POINT
Atomic model building
IDProtocolSpace
1FLEXIBLE FITREAL
2
Atomic model building

Source name: PDB / Type: experimental model

IDPDB-ID 3D fitting-IDAccession codeChain residue rangeInitial refinement model-IDPdb chain residue range
18ACT

8act

18ACT4-87514-875
22FXM

2fxm

22FXM838-9432838-943
RefinementHighest resolution: 4.5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00319991
ELECTRON MICROSCOPYf_angle_d0.60126889
ELECTRON MICROSCOPYf_dihedral_angle_d6.5372645
ELECTRON MICROSCOPYf_chiral_restr0.0392900
ELECTRON MICROSCOPYf_plane_restr0.0053494

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