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- PDB-8act: structure of the human beta-cardiac myosin folded-back off state -

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Basic information

Entry
Database: PDB / ID: 8act
Titlestructure of the human beta-cardiac myosin folded-back off state
Components
  • Myosin light chain 3
  • Myosin regulatory light chain 2, ventricular/cardiac muscle isoform
  • Myosin-7
KeywordsCONTRACTILE PROTEIN / Cardiac Myosin / Myosin / Human / folded-back off state
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 / cardiac myofibril / muscle myosin complex / regulation of striated muscle contraction / cardiac myofibril assembly / muscle filament sliding / 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 / cardiac myofibril / muscle myosin complex / regulation of striated muscle contraction / cardiac myofibril assembly / muscle filament sliding / regulation of the force of heart contraction / transition between fast and slow fiber / myosin filament / myosin II complex / adult heart development / cardiac muscle hypertrophy in response to stress / Striated Muscle Contraction / positive regulation of ATP-dependent activity / I band / myosin complex / A band / structural constituent of muscle / sarcomere organization / microfilament motor activity / ventricular cardiac muscle tissue morphogenesis / myofibril / myosin heavy chain binding / heart contraction / positive regulation of the force of heart contraction / skeletal muscle contraction / actin monomer binding / striated muscle contraction / stress fiber / ATP metabolic process / cardiac muscle contraction / regulation of heart rate / sarcomere / muscle contraction / negative regulation of cell growth / Z disc / actin filament binding / heart development / cytoskeleton / calmodulin binding / calcium ion binding / ATP binding / cytosol / cytoplasm
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. / Myosin head, motor domain / Myosin head (motor 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. / Myosin head, motor domain / Myosin head (motor domain) / Myosin motor domain profile. / Myosin. Large ATPases. / IQ motif profile. / IQ motif, EF-hand binding site / 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: 3.6 Å
AuthorsGrinzato, A. / Kandiah, E. / Robert-Paganin, J. / Auguin, D. / Kikuti, C. / Nandwani, N. / Moussaoui, D. / Pathak, D. / Ruppel, K.M. / Spudich, J.A. / Houdusse, A.
Funding support United States, France, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIH-RM1GM131981-01 United States
Agence Nationale de la Recherche (ANR)ANR-21-CE11-0022-01 France
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIH-R01GM33289 United States
CitationJournal: Nat Commun / Year: 2023
Title: Cryo-EM structure of the folded-back state of human β-cardiac myosin.
Authors: Alessandro Grinzato / Daniel Auguin / Carlos Kikuti / Neha Nandwani / Dihia Moussaoui / Divya Pathak / Eaazhisai Kandiah / Kathleen M Ruppel / James A Spudich / Anne Houdusse / Julien Robert-Paganin /
Abstract: To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' ...To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an 'off' state that can be converted to an 'on' state when exertion is increased. The 'off' state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 Å resolution, providing details of all the interfaces stabilizing the 'off' state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the 'off' state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability.
History
DepositionJul 6, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 30, 2023Group: Data collection / Structure summary
Category: audit_author / chem_comp_atom ...audit_author / chem_comp_atom / chem_comp_bond / em_author_list

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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)277,47912
Polymers276,3866
Non-polymers1,0936
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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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: 103807.148 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYH7, MYHCB / Production host: Homo sapiens (human) / 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: 17895.398 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MYL3 / Production host: Homo sapiens (human) / References: UniProt: P08590
#3: Protein Myosin regulatory light chain 2, ventricular/cardiac muscle isoform


Mass: 16490.580 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P10916

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Non-polymers , 3 types, 6 molecules

#4: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE / Adenosine 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 / Phosphate


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

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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: human beta-cardiac myosin folded-back off state / Type: COMPLEX / Entity ID: #1-#3 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 0.3 mg/ml / Embedding 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 FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 213596 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00219201
ELECTRON MICROSCOPYf_angle_d0.58625849
ELECTRON MICROSCOPYf_dihedral_angle_d5.4892534
ELECTRON MICROSCOPYf_chiral_restr0.0412795
ELECTRON MICROSCOPYf_plane_restr0.0043345

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