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- PDB-8g4l: Cryo-EM structure of the human cardiac myosin filament -

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Basic information

Entry
Database: PDB / ID: 8g4l
TitleCryo-EM structure of the human cardiac myosin filament
Components
  • Myosin light chain 3
  • Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
  • Myosin-7
  • Myosin-binding protein C, cardiac-type
  • Titin
KeywordsCONTRACTILE PROTEIN / cardiac / myosin / filament / complex
Function / homology
Function and homology information


myosin II heavy chain binding / C zone / regulation of muscle filament sliding / muscle cell fate specification / striated muscle myosin thick filament / regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / sarcomerogenesis / titin-telethonin complex / structural molecule activity conferring elasticity ...myosin II heavy chain binding / C zone / regulation of muscle filament sliding / muscle cell fate specification / striated muscle myosin thick filament / regulation of slow-twitch skeletal muscle fiber contraction / regulation of the force of skeletal muscle contraction / sarcomerogenesis / titin-telethonin complex / structural molecule activity conferring elasticity / skeletal muscle myosin thick filament assembly / telethonin binding / regulation of striated muscle contraction / cardiac myofibril / detection of muscle stretch / muscle myosin complex / protein kinase A signaling / muscle alpha-actinin binding / cardiac myofibril assembly / regulation of the force of heart contraction / transition between fast and slow fiber / myosin filament / mitotic chromosome condensation / cardiac muscle hypertrophy / adult heart development / cardiac muscle tissue morphogenesis / positive regulation of ATP-dependent activity / cardiac muscle hypertrophy in response to stress / actinin binding / Striated Muscle Contraction / muscle filament sliding / protein kinase regulator activity / M band / myosin complex / myosin II complex / A band / I band / cardiac muscle cell development / structural constituent of muscle / sarcomere organization / ventricular cardiac muscle tissue morphogenesis / microfilament motor activity / myosin heavy chain binding / heart contraction / myosin binding / positive regulation of the force of heart contraction / myofibril / ATPase activator activity / striated muscle thin filament / skeletal muscle thin filament assembly / actin monomer binding / skeletal muscle contraction / striated muscle contraction / ATP metabolic process / heart morphogenesis / stress fiber / cardiac muscle contraction / titin binding / muscle contraction / regulation of heart rate / sarcomere / condensed nuclear chromosome / positive regulation of protein secretion / negative regulation of cell growth / Z disc / response to calcium ion / actin filament binding / Platelet degranulation / actin binding / heart development / protease binding / protein tyrosine kinase activity / eukaryotic translation initiation factor 2alpha kinase activity / cytoskeleton / 3-phosphoinositide-dependent protein kinase activity / DNA-dependent protein kinase activity / ribosomal protein S6 kinase activity / histone H3S10 kinase activity / histone H2AXS139 kinase activity / histone H3S28 kinase activity / histone H4S1 kinase activity / histone H2BS14 kinase activity / histone H3T3 kinase activity / histone H2AS121 kinase activity / Rho-dependent protein serine/threonine kinase activity / histone H2BS36 kinase activity / histone H3S57 kinase activity / histone H2AT120 kinase activity / AMP-activated protein kinase activity / histone H2AS1 kinase activity / histone H3T6 kinase activity / histone H3T11 kinase activity / histone H3T45 kinase activity / non-specific serine/threonine protein kinase / calmodulin binding / cell adhesion / protein serine kinase activity / protein serine/threonine kinase activity / calcium ion binding / positive regulation of gene expression
Similarity search - Function
PPAK motif / : / PPAK motif / Titin, Z repeat / Titin Z / : / MyBP-C, tri-helix bundle domain / Tri-helix bundle domain / DNA repair protein XRCC4-like, C-terminal / Myosin tail ...PPAK motif / : / PPAK motif / Titin, Z repeat / Titin Z / : / MyBP-C, tri-helix bundle domain / Tri-helix bundle 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. / Immunoglobulin I-set / Immunoglobulin I-set domain / Kinesin motor domain superfamily / : / Fibronectin type III domain / Fibronectin type 3 domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin V-Type / EF-hand domain pair / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / EF-hand, calcium binding motif / Immunoglobulin V-set domain / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase domain / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 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 / Myosin-binding protein C, cardiac-type / Titin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.4 Å
AuthorsDutta, D. / Nguyen, V. / Padron, R. / Craig, R.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)AR072036 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL139883 United States
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: Nature / Year: 2023
Title: Cryo-EM structure of the human cardiac myosin filament.
Authors: Debabrata Dutta / Vu Nguyen / Kenneth S Campbell / Raúl Padrón / Roger Craig /
Abstract: Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin- ...Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin's motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state; how titin and cMyBP-C may contribute to length-dependent activation; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
History
DepositionFeb 10, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 1, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Dec 6, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
BB: Myosin-7
BA: Myosin-7
BE: Myosin light chain 3
BF: Myosin light chain 3
BG: Myosin-7
BH: Myosin-7
BI: Myosin-7
BJ: Myosin-7
BK: Myosin-7
BL: Myosin-7
BM: Myosin-7
BN: Myosin-7
BO: Myosin-7
BP: Myosin-7
BQ: Myosin-7
BR: Myosin-7
BS: Myosin-7
BT: Myosin-7
BU: Myosin-7
BV: Myosin-7
BW: Myosin-7
BX: Myosin-7
BY: Myosin-7
BZ: Myosin-7
ba: Myosin light chain 3
bb: Myosin light chain 3
bc: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
bd: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
be: Myosin-7
bf: Myosin-7
bg: Myosin light chain 3
bh: Myosin light chain 3
bi: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
bj: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
bk: Myosin-7
bl: Myosin-7
bm: Titin
bn: Titin
bo: Myosin-binding protein C, cardiac-type
bq: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
br: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
AA: Myosin-7
AB: Myosin-7
AE: Myosin light chain 3
AF: Myosin light chain 3
AG: Myosin-7
AH: Myosin-7
AI: Myosin-7
AJ: Myosin-7
AK: Myosin-7
AL: Myosin-7
AM: Myosin-7
AN: Myosin-7
AO: Myosin-7
AP: Myosin-7
AQ: Myosin-7
AR: Myosin-7
AS: Myosin-7
AT: Myosin-7
AU: Myosin-7
AV: Myosin-7
AW: Myosin-7
AX: Myosin-7
AY: Myosin-7
AZ: Myosin-7
aa: Myosin light chain 3
ab: Myosin light chain 3
ac: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
ad: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
ae: Myosin-7
af: Myosin-7
ag: Myosin light chain 3
ah: Myosin light chain 3
ai: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
aj: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
ak: Myosin-7
al: Myosin-7
am: Titin
an: Titin
ao: Myosin-binding protein C, cardiac-type
aq: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
ar: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
A: Myosin-7
B: Myosin-7
E: Myosin light chain 3
F: Myosin light chain 3
G: Myosin-7
H: Myosin-7
I: Myosin-7
J: Myosin-7
K: Myosin-7
L: Myosin-7
M: Myosin-7
N: Myosin-7
O: Myosin-7
P: Myosin-7
Q: Myosin-7
R: Myosin-7
S: Myosin-7
T: Myosin-7
U: Myosin-7
V: Myosin-7
W: Myosin-7
X: Myosin-7
Y: Myosin-7
Z: Myosin-7
a: Myosin light chain 3
b: Myosin light chain 3
c: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
d: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
e: Myosin-7
f: Myosin-7
g: Myosin light chain 3
h: Myosin light chain 3
i: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
j: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
k: Myosin-7
l: Myosin-7
m: Titin
n: Titin
o: Myosin-binding protein C, cardiac-type
q: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
r: Myosin regulatory light chain 2, ventricular/cardiac muscle isoform


Theoretical massNumber of molelcules
Total (without water)19,304,216123
Polymers19,304,216123
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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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: 223445.984 Da / Num. of mol.: 78 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: heart / 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 / Essential light chain


Mass: 21962.068 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: heart / References: UniProt: P08590
#3: Protein
Myosin regulatory light chain 2, ventricular/cardiac muscle isoform / MLC-2v / Cardiac myosin light chain 2 / Myosin light chain 2 / slow skeletal/ventricular muscle ...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.: 18 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: heart / References: UniProt: P10916
#4: Protein
Titin / Connectin / Rhabdomyosarcoma antigen MU-RMS-40.14


Mass: 119771.961 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: heart
References: UniProt: Q8WZ42, non-specific serine/threonine protein kinase
#5: Protein Myosin-binding protein C, cardiac-type / Cardiac MyBP-C / C-protein / cardiac muscle isoform


Mass: 140947.172 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: heart / References: UniProt: Q14896
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Myosin filaments isolated from human cardiac left ventricular muscle
Type: TISSUE / Entity ID: all / Source: NATURAL
Molecular weightValue: 5.9 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 6.8
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: FEI TITAN 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
Image recordingElectron dose: 61 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.20.1_4487refinement
PHENIX1.20.1_4487refinement
EM software
IDNameVersionCategory
4cryoSPARC3.3.2CTF correction
7UCSF ChimeraX1.4model fitting
8MDFFmodel fitting
9Coot0.9.5model fitting
10ISOLDE1.4model fitting
12cryoSPARC3.3.2initial Euler assignment
13cryoSPARC3.3.2final Euler assignment
22PHENIX1.19.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 6.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102581 / Symmetry type: POINT
Atomic model building
IDProtocolSpace
1FLEXIBLE FITREAL
2
3
4
5
6
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
11
25N69

5n69

25N691PDBexperimental model
32FXO

2fxo

22FXO2PDBexperimental model
42AF-P12883-F1-model_v13AlphaFoldin silico model
52AF-P10916-F1-model_v34AlphaFoldin silico model
62Q8WZ425AlphaFoldin silico model
75N69

5n69

35N691PDBexperimental model
82FXO

2fxo

32FXO2PDBexperimental model
93AF-P12883-F1-model_v13AlphaFoldin silico model
103AF-P10916-F1-model_v34AlphaFoldin silico model
113Q8WZ425AlphaFoldin silico model
125N69

5n69

45N691PDBexperimental model
132FXO

2fxo

42FXO2PDBexperimental model
144AF-P12883-F1-model_v13AlphaFoldin silico model
154AF-P10916-F1-model_v34AlphaFoldin silico model
164Q8WZ425AlphaFoldin silico model
175N69

5n69

55N691PDBexperimental model
182FXO

2fxo

52FXO2PDBexperimental model
195AF-P12883-F1-model_v13AlphaFoldin silico model
205AF-P10916-F1-model_v34AlphaFoldin silico model
215Q8WZ425AlphaFoldin silico model
225N69

5n69

65N691PDBexperimental model
232FXO

2fxo

62FXO2PDBexperimental model
246AF-P12883-F1-model_v13AlphaFoldin silico model
256AF-P10916-F1-model_v34AlphaFoldin silico model
266Q8WZ425AlphaFoldin silico model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 356.06 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0055419322
ELECTRON MICROSCOPYf_angle_d0.6869563082
ELECTRON MICROSCOPYf_chiral_restr0.040662370
ELECTRON MICROSCOPYf_plane_restr0.005174154
ELECTRON MICROSCOPYf_dihedral_angle_d5.093755374

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