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- EMDB-56106: Human Cardiac Interacting Heads Motif, E525K mutant -

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Basic information

Entry
Database: EMDB / ID: EMD-56106
TitleHuman Cardiac Interacting Heads Motif, E525K mutant
Map dataSharpened map
Sample
  • Complex: Interacting Heads Motif
    • Protein or peptide: Myosin-7
    • Protein or peptide: Myosin light chain 3
    • Protein or peptide: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHATE ION
  • Ligand: MAGNESIUM ION
KeywordsCardiac / myosin / thick filament / interacting-heads motif / IHM / beta-cardiac myosin / E525K / MOTOR PROTEIN
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
Myosin light chain 3 / Myosin regulatory light chain 2, ventricular/cardiac muscle isoform / Myosin-7
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsLannes L / Kikuti CM / Auguin D / Robert-Paganin J / Houdusse A
Funding support United States, France, 3 items
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, 2025-
Header (metadata) releaseJun 17, 2026-
Map releaseJun 17, 2026-
UpdateJun 17, 2026-
Current statusJun 17, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_56106.png

Downloads & links

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Map

FileDownload / File: emd_56106.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.17 Å/pix.
x 300 pix.
= 352.38 Å		1.17 Å/pix.
x 300 pix.
= 352.38 Å		1.17 Å/pix.
x 300 pix.
= 352.38 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1746 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.126
Minimum - Maximum-1.3523281 - 2.356417
Average (Standard dev.)-0.00024340977 (±0.031463724)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 352.38 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B

Fileemd_56106_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_56106_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Interacting Heads Motif

EntireName: Interacting Heads Motif
Components
  • Complex: Interacting Heads Motif
    • Protein or peptide: Myosin-7
    • Protein or peptide: Myosin light chain 3
    • Protein or peptide: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: PHOSPHATE ION
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Interacting Heads Motif

SupramoleculeName: Interacting Heads Motif / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: Cardiac myosin in its inactive ("OFF-"; "back folded") state
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: 223.530203 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGDSEMAVFG AAAPYLRKSE KERLEAQTRP FDLKKDVFVP DDKQEFVKAK IVSREGGKVT AETEYGKTVT VKEDQVMQQN PPKFDKIED MAMLTFLHEP AVLYNLKDRY GSWMIYTYSG LFCVTVNPY(M3L) WLPVYTPEVV AAYRGKKRSE APPHIFS IS DNAYQYMLTD ...String:
MGDSEMAVFG AAAPYLRKSE KERLEAQTRP FDLKKDVFVP DDKQEFVKAK IVSREGGKVT AETEYGKTVT VKEDQVMQQN PPKFDKIED MAMLTFLHEP AVLYNLKDRY GSWMIYTYSG LFCVTVNPY(M3L) WLPVYTPEVV AAYRGKKRSE APPHIFS IS DNAYQYMLTD RENQSILITG ESGAGKTVNT KRVIQYFAVI AAIGDRSKKD QSPGKGTLED QIIQANPALE AFGNAKTV R NDNSSRFGKF IRIHFGATGK LASADIETYL LEKSRVIFQL KAERDYHIFY QILSNKKPEL LDMLLITNNP YDYAFISQG ETTVASIDDA EELMATDNAF DVLGFTSEEK NSMYKLTGAI MHFGNMKFKL KQREEQAEPD GTEEADKSAY LMGLNSADLL KGLCHPRVK VGNEYVTKGQ NVQQVIYATG ALAKAVYERM FNWMVTRINA TLETKQPRQY FIGVLDIAGF EIFDFNSFEQ L CINFTNEK LQQFFNHHMF VLEQEEYKKE GIEWTFIDFG MDLQACIDLI KKPMGIMSIL EEECMFPKAT DMTF(M3L)AKL F DNHLGKSANF QKPRNIKGKP EAHFSLIHYA GIVDYNIIGW LQKNKDPLNE TVVGLYQKSS LKLLSTLFAN YAGADAPIE KGKGKAKKGS SFQTVSALHR ENLNKLMTNL RSTHPHFVRC IIPNETKSPG VMDNPLVMHQ LRCNGVLEGI RICRKGFPNR ILYGDFRQR YRILNPAAIP EGQFIDSRKG AEKLLSSLDI DHNQYKFGHT KVFFKAGLLG LLEEMRDERL SRIITRIQAQ S RGVLARME YKKLLERRDS LLVIQWNIRA FMGVKNWPWM KLYFKIKPLL KSAEREKEMA SMKEEFTRLK EALEKSEARR KE LEEKMVS LLQEKNDLQL QVQAEQDNLA DAEERCDQLI KNKIQLEAKV KEMNERLEDE EEMNAELTAK KRKLEDECSE LKR DIDDLE LTLAKVEKEK HATENKVKNL TEEMAGLDEI IAKLTKEKKA LQEAHQQALD DLQAEEDKVN TLTKAKVKLE QQVD DLEGS LEQEKKVRMD LERAKRKLEG DLKLTQESIM DLENDKQQLD ERLKKKDFEL NALNARIEDE QALGSQLQKK LKELQ ARIE ELEEELEAER TARAKVEKLR SDLSRELEEI SERLEEAGGA TSVQIEMNKK REAEFQKMRR DLEEATLQHE ATAAAL RKK HADSVAELGE QIDNLQRVKQ KLEKEKSEFK LELDDVTSNM EQIIKAKANL EKMCRTLEDQ MNEHRSKAEE TQRSVND LT SQRAKLQTEN GELSRQLDEK EALISQLTRG KLTYTQQLED LKRQLEEEVK AKNALAHALQ SARHDCDLLR EQYEEETE A KAELQRVLSK ANSEVAQWRT KYETDAIQRT EELEEAKKKL AQRLQEAEEA VEAVNAKCSS LEKTKHRLQN EIEDLMVDV ERSNAAAAAL DKKQRNFDKI LAEWKQKYEE SQSELESSQK EARSLSTELF KLKNAYEESL EHLETFKREN KNLQEEISDL TEQLGSSGK TIHELEKVRK QLEAEKMELQ SALEEAEASL EHEEGKILRA QLEFNQIKAE IERKLAEKDE EMEQAKRNHL R VVDSLQTS LDAETRSRNE ALRVKKKMEG DLNEMEIQLS HANRMAAEAQ KQVKSLQSLL KDTQIQLDDA VRANDDLKEN IA IVERRNN LLQAELEELR AVVEQTERSR KLAEQELIET SERVQLLHSQ NTSLINQKKK MDADLSQLQT EVEEAVQECR NAE EKAKKA ITDAAMMAEE LKKEQDTSAH LERMKKNMEQ TIKDLQHRLD EAEQIALKGG KKQLQKLEAR VRELENELEA EQKR NAESV KGMRKSERRI KELTYQTEED RKNLLRLQDL VDKLQLKVKA YKRQAEEAEE QANTNLSKFR KVQHELDEAE ERADI AESQ VNKLRAKSRD IGTKGLNEE

UniProtKB: Myosin-7

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Macromolecule #2: Myosin light chain 3

MacromoleculeName: Myosin light chain 3 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.962068 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAPKKPEPKK DDAKAAPKAA PAPAPPPEPE RPKEVEFDAS KIKIEFTPEQ IEEFKEAFML FDRTPKCEMK ITYGQCGDVL RALGQNPTQ AEVLRVLGKP RQEELNTKMM DFETFLPMLQ HISKNKDTGT YEDFVEGLRV FDKEGNGTVM GAELRHVLAT L GERLTEDE ...String:
MAPKKPEPKK DDAKAAPKAA PAPAPPPEPE RPKEVEFDAS KIKIEFTPEQ IEEFKEAFML FDRTPKCEMK ITYGQCGDVL RALGQNPTQ AEVLRVLGKP RQEELNTKMM DFETFLPMLQ HISKNKDTGT YEDFVEGLRV FDKEGNGTVM GAELRHVLAT L GERLTEDE VEKLMAGQED SNGCINYEAF VKHIMSS

UniProtKB: Myosin light chain 3

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Macromolecule #3: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform

MacromoleculeName: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.813273 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MAPKKAKKRA GGANSNVFSM FEQTQIQEFK EAFTIMDQNR DGFIDKNDLR DTFAALGRVN VKNEEIDEMI KEAPGPINFT VFLTMFGEK LKGADPEETI LNAFKVFDPE GKGVLKADYV REMLTTQAER FSKEEVDQMF AAFPPDVTGN LDYKNLVHII T HGEEKD

UniProtKB: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform

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Macromolecule #4: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 4 / 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 #5: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION

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Macromolecule #6: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 680000
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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