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- PDB-9tpj: Human Cardiac Interacting Heads Motif, E525K mutant -

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Basic information

Entry
Database: PDB / ID: 9tpj
TitleHuman Cardiac Interacting Heads Motif, E525K mutant
Components
  • Myosin light chain 3
  • Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
  • Myosin-7
KeywordsMOTOR PROTEIN / Cardiac / myosin / thick filament / interacting-heads motif / IHM / beta-cardiac myosin / E525K
Function / homology
Function and homology information


myosin II heavy chain binding / muscle cell fate specification / regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / regulation of striated muscle contraction / cardiac myofibril / muscle myosin complex / A band / cardiac myofibril assembly / regulation of the force of heart contraction ...myosin II heavy chain binding / muscle cell fate specification / regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / regulation of striated muscle contraction / cardiac myofibril / muscle myosin complex / A band / cardiac myofibril assembly / regulation of the force of heart contraction / transition between fast and slow fiber / myosin filament / Striated Muscle Contraction / muscle filament sliding / cardiac muscle hypertrophy in response to stress / adult heart development / myosin complex / myosin II complex / I band / structural constituent of muscle / ventricular cardiac muscle tissue morphogenesis / microfilament motor activity / myosin heavy chain binding / heart contraction / positive regulation of the force of heart contraction / myofibril / cytoskeletal motor activity / actin monomer binding / skeletal muscle tissue development / ATP metabolic process / striated muscle contraction / skeletal muscle contraction / cardiac muscle contraction / stress fiber / regulation of heart rate / muscle contraction / post-embryonic development / sarcomere / negative regulation of cell growth / Z disc / actin filament binding / heart development / cytoskeleton / calmodulin binding / calcium ion binding / ATP binding / cytoplasm / cytosol
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 ...: / 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 motor domain profile. / Myosin head, motor domain / Myosin head (motor domain) / Myosin. Large ATPases. / IQ motif profile. / Kinesin motor domain superfamily / : / EF-hand domain pair / 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
ADENOSINE-5'-DIPHOSPHATE / PHOSPHATE ION / Myosin light chain 3 / Myosin regulatory light chain 2, ventricular/cardiac muscle isoform / Myosin-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsLannes, L. / Kikuti, C.M. / Auguin, D. / Robert-Paganin, J. / Houdusse, A.
Funding support United States, France, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)RM1GM131981-01 United States
Agence Nationale de la Recherche (ANR)ANR-21-CE11-0022-01 France
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01GM33289 United States
CitationJournal: Nat Commun / Year: 2026
Title: Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis.
Authors: Daniel Auguin / Laurie Lannes / Carlos Kikuti / Nour Ayoub / Marie Juillé / Stéphane Réty / Neha Nandwani / Divya Pathak / Kathleen M Ruppel / James A Spudich / Julien Robert-Paganin / Anne Houdusse /
Abstract: Cardiac contractility requires precise regulation. A recently discovered form of regulation of cardiac contractility involves a β-cardiac myosin off-state, the Interacting-Heads Motif (IHM). Despite ...Cardiac contractility requires precise regulation. A recently discovered form of regulation of cardiac contractility involves a β-cardiac myosin off-state, the Interacting-Heads Motif (IHM). Despite its central role in cardiac physiology and disease, IHM structural dynamics remain poorly understood. Here, we integrate near-atomic resolution cryo-EM with all-atom molecular dynamics to characterize IHM in solution and in the context of the filament. We describe its conformational ensembles maintained by dynamic interfaces, and the stabilizing effect of the dilated cardiomyopathy mutation E525K, which limits S2 coiled-coil flexibility and impairs myosin activation. Intrinsically disordered regions of IHM and MyBP-C further modulate these dynamics. Our findings provide evidence for how IHM ensembles balance off/on states and anchor myosin heads in distinct thick filament environments. This integrated structural and dynamic approach enhances the understanding of thick filament regulation and facilitates predictions of the effects of genetic variants in inherited cardiomyopathies.
History
DepositionDec 18, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 17, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 17, 2026Data 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
B: Myosin-7
C: Myosin light chain 3
D: Myosin light chain 3
E: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
F: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)529,70412
Polymers528,6116
Non-polymers1,0936
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

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Protein , 3 types, 6 molecules ABCDEF

#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: 223530.203 Da / Num. of mol.: 2 / Mutation: E525K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYH7, MYHCB / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P12883
#2: Protein Myosin light chain 3 / Cardiac myosin light chain 1 / CMLC1 / Myosin light chain 1 / slow-twitch muscle B/ventricular ...Cardiac myosin light chain 1 / CMLC1 / Myosin light chain 1 / slow-twitch muscle B/ventricular isoform / MLC1SB / Ventricular myosin alkali light chain / Ventricular myosin light chain 1 / VLCl / Ventricular/slow twitch myosin alkali light chain / MLC-lV/sb


Mass: 21962.068 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYL3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08590
#3: Protein Myosin regulatory light chain 2, ventricular/cardiac muscle isoform / MLC-2 / MLC-2v / Cardiac myosin light chain 2 / Myosin light chain 2 / slow skeletal/ventricular ...MLC-2 / MLC-2v / Cardiac myosin light chain 2 / Myosin light chain 2 / slow skeletal/ventricular muscle isoform / MLC-2s/v / Ventricular myosin light chain 2


Mass: 18813.273 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYL2, MLC2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P10916

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Non-polymers , 3 types, 6 molecules

#4: 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
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg

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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

ComponentName: Interacting Heads Motif / Type: COMPLEX
Details: Cardiac myosin in its inactive ("OFF-"; "back folded") state
Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen 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: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 680000 / Symmetry type: POINT

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