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- PDB-7mi1: X-ray structure of yeast dynein motor domain in the presence of a... -

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Basic information

Entry
Database: PDB / ID: 7mi1
TitleX-ray structure of yeast dynein motor domain in the presence of a pyrazolo-pyrimidinone-based compound (compound 20)
ComponentsChimera protein of Dynein and Endolysin
KeywordsMOTOR PROTEIN / AAA ATPase / ATPase inhibitor
Function / homology
Function and homology information


karyogamy / establishment of mitotic spindle localization / astral microtubule / nuclear migration along microtubule / minus-end-directed microtubule motor activity / cytoplasmic dynein complex / dynein light intermediate chain binding / spindle pole body / nuclear migration / dynein intermediate chain binding ...karyogamy / establishment of mitotic spindle localization / astral microtubule / nuclear migration along microtubule / minus-end-directed microtubule motor activity / cytoplasmic dynein complex / dynein light intermediate chain binding / spindle pole body / nuclear migration / dynein intermediate chain binding / mitotic sister chromatid segregation / establishment of mitotic spindle orientation / cytoplasmic microtubule / cytoplasmic microtubule organization / viral release from host cell by cytolysis / Neutrophil degranulation / peptidoglycan catabolic process / mitotic spindle organization / cell wall macromolecule catabolic process / lysozyme / lysozyme activity / cell cortex / host cell cytoplasm / defense response to bacterium / ATP hydrolysis activity / ATP binding / cytoplasm
Similarity search - Function
: / DYN1, AAA+ ATPase lid domain / Dynein heavy chain 3, AAA+ lid domain / AAA+ lid domain / P-loop containing dynein motor region / Dynein heavy chain, tail / Dynein heavy chain, N-terminal region 1 / Dynein heavy chain / Dynein heavy chain region D6 P-loop domain / Dynein heavy chain, linker ...: / DYN1, AAA+ ATPase lid domain / Dynein heavy chain 3, AAA+ lid domain / AAA+ lid domain / P-loop containing dynein motor region / Dynein heavy chain, tail / Dynein heavy chain, N-terminal region 1 / Dynein heavy chain / Dynein heavy chain region D6 P-loop domain / Dynein heavy chain, linker / Dynein heavy chain, AAA module D4 / Dynein heavy chain, coiled coil stalk / Dynein heavy chain, hydrolytic ATP-binding dynein motor region / Dynein heavy chain, ATP-binding dynein motor region / Dynein heavy chain AAA lid domain / Dynein heavy chain AAA lid domain superfamily / Dynein heavy chain, domain 2, N-terminal / Dynein heavy chain, linker, subdomain 3 / Dynein heavy chain, AAA1 domain, small subdomain / Dynein heavy chain region D6 P-loop domain / Dynein heavy chain, N-terminal region 2 / Hydrolytic ATP binding site of dynein motor region / Microtubule-binding stalk of dynein motor / P-loop containing dynein motor region D4 / ATP-binding dynein motor region / Dynein heavy chain AAA lid domain / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / Lysozyme-like domain superfamily / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Endolysin / Dynein heavy chain, cytoplasmic
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.5 Å
AuthorsSantarossa, C.C. / Ekiert, D.C. / Bhabha, G. / Kapoor, T.M.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM98579 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM130234-01 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R00GM112982 United States
Damon Runyon Cancer Research FoundationDFS-20-16 United States
CitationJournal: Cell Chem Biol / Year: 2021
Title: Targeting allostery in the Dynein motor domain with small molecule inhibitors.
Authors: Cristina C Santarossa / Keith J Mickolajczyk / Jonathan B Steinman / Linas Urnavicius / Nan Chen / Yasuhiro Hirata / Yoshiyuki Fukase / Nicolas Coudray / Damian C Ekiert / Gira Bhabha / Tarun M Kapoor /
Abstract: Cytoplasmic dyneins are AAA (ATPase associated with diverse cellular activities) motor proteins responsible for microtubule minus-end-directed intracellular transport. Dynein's unusually large size, ...Cytoplasmic dyneins are AAA (ATPase associated with diverse cellular activities) motor proteins responsible for microtubule minus-end-directed intracellular transport. Dynein's unusually large size, four distinct nucleotide-binding sites, and conformational dynamics pose challenges for the design of potent and selective chemical inhibitors. Here we use structural approaches to develop a model for the inhibition of a well-characterized S. cerevisiae dynein construct by pyrazolo-pyrimidinone-based compounds. These data, along with functional assays of dynein motility and mutagenesis studies, suggest that the compounds inhibit dynein by engaging the regulatory ATPase sites in the AAA3 and AAA4 domains, and not by interacting with dynein's main catalytic site in the AAA1 domain. A double Walker B mutation of the AAA3 and AAA4 sites substantially reduces enzyme activity, suggesting that targeting these regulatory domains is sufficient to inhibit dynein. Our findings reveal how chemical inhibitors can be designed to disrupt allosteric communication across dynein's AAA domains.
History
DepositionApr 16, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 26, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 2, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 3, 2021Group: Database references / Category: citation / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Chimera protein of Dynein and Endolysin


Theoretical massNumber of molelcules
Total (without water)304,8901
Polymers304,8901
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)135.065, 157.917, 179.309
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)

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Components

#1: Protein Chimera protein of Dynein and Endolysin /


Mass: 304889.875 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: DYN1, DHC1, YKR054C, e, T4Tp126 / Production host: Saccharomyces cerevisiae (brewer's yeast) / Strain (production host): VY972 / References: UniProt: P36022, UniProt: D9IEF7

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.17 Å3/Da / Density % sol: 61.19 % / Description: Flat and clear
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop
Details: 100 mM Bis-Tris pH 6.9, 200 mM sodium acetate, 12% PEG 3350, and 10 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.92009 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 31, 2018
RadiationMonochromator: horizontal bounce Si 111 double crystal monochromator
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92009 Å / Relative weight: 1
ReflectionResolution: 4.5→47.66 Å / Num. obs: 23226 / % possible obs: 99.5 % / Redundancy: 6.8 % / Biso Wilson estimate: 183.01 Å2 / CC1/2: 0.995 / Net I/σ(I): 5.99
Reflection shellResolution: 4.5→4.77 Å / Redundancy: 6.5 % / Mean I/σ(I) obs: 1.13 / CC1/2: 0.484 / % possible all: 98.3

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Coot0.8.9.2model building
XSCALE20180319data scaling
PDB_EXTRACTdata extraction
XDS20180319data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4AI6

4ai6


Resolution: 4.5→47.66 Å / SU ML: 0.9176 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 37.3123
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflectionSelection details
Rfree0.3197 1997 8.61 %Random
Rwork0.2757 21190 --
obs0.2795 23187 99.54 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 207.43 Å2
Refinement stepCycle: LAST / Resolution: 4.5→47.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms21212 0 0 0 21212
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002721632
X-RAY DIFFRACTIONf_angle_d0.573829225
X-RAY DIFFRACTIONf_chiral_restr0.03953313
X-RAY DIFFRACTIONf_plane_restr0.0043697
X-RAY DIFFRACTIONf_dihedral_angle_d13.39352821
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
4.5-4.620.43711340.36971424X-RAY DIFFRACTION95.47
4.62-4.740.33071390.33931474X-RAY DIFFRACTION100
4.74-4.880.36511410.36791500X-RAY DIFFRACTION100
4.88-5.040.38221410.34761490X-RAY DIFFRACTION100
5.04-5.220.37431420.34361516X-RAY DIFFRACTION100
5.22-5.430.37471410.33731491X-RAY DIFFRACTION100
5.43-5.670.36791420.33661511X-RAY DIFFRACTION100
5.67-5.970.36211430.34441515X-RAY DIFFRACTION100
5.97-6.340.39011420.35811509X-RAY DIFFRACTION100
6.34-6.830.3581440.32811520X-RAY DIFFRACTION100
6.83-7.520.34811450.29231536X-RAY DIFFRACTION100
7.52-8.60.31681430.24661531X-RAY DIFFRACTION100
8.6-10.810.23071480.18311555X-RAY DIFFRACTION99.82
10.82-47.660.28651520.22621618X-RAY DIFFRACTION98.33
Refinement TLS params.Method: refined / Origin x: 45.6099861602 Å / Origin y: 52.0343880284 Å / Origin z: 29.0908856623 Å
111213212223313233
T1.49019985644 Å20.0535763362696 Å20.0825432394223 Å2-1.61029247889 Å20.172512408184 Å2--1.79177705312 Å2
L0.743167399298 °2-0.171533538266 °2-0.199200474746 °2-0.761019033694 °20.516708308953 °2--0.950102488402 °2
S0.0827105672919 Å °0.102989224065 Å °0.0707224066012 Å °-0.320943328927 Å °-0.0354869029444 Å °0.00193908771601 Å °-0.263059471329 Å °-0.229057331041 Å °-0.056745506107 Å °
Refinement TLS groupSelection details: all

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