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- PDB-6ls4: A novel anti-tumor agent S-40 in complex with tubulin -

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Basic information

Entry
Database: PDB / ID: 6ls4
TitleA novel anti-tumor agent S-40 in complex with tubulin
Components
  • Stathmin
  • Tubulin alpha-1B chain
  • Tubulin beta chain
KeywordsSTRUCTURAL PROTEIN / mitosis / ANTITUMOR PROTEIN
Function / homology
Function and homology information


Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins / PKR-mediated signaling ...Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins / PKR-mediated signaling / Resolution of Sister Chromatid Cohesion / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Separation of Sister Chromatids / The role of GTSE1 in G2/M progression after G2 checkpoint / Aggrephagy / Recruitment of NuMA to mitotic centrosomes / RHO GTPases activate IQGAPs / RHO GTPases Activate Formins / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / COPI-independent Golgi-to-ER retrograde traffic / MHC class II antigen presentation / COPI-mediated anterograde transport / microtubule depolymerization / regulation of microtubule polymerization or depolymerization / tubulin binding / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / structural constituent of cytoskeleton / microtubule cytoskeleton organization / neuron projection development / microtubule cytoskeleton / mitotic cell cycle / microtubule / neuron projection / GTPase activity / GTP binding / metal ion binding / cytoplasm
Similarity search - Function
Stathmin-4 / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. / Tubulin-beta mRNA autoregulation signal. / Alpha tubulin ...Stathmin-4 / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. / Tubulin-beta mRNA autoregulation signal. / Alpha tubulin / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Tubulin/FtsZ family, C-terminal domain / Tubulin/FtsZ-like, C-terminal domain / Tubulin/FtsZ, C-terminal / Tubulin/FtsZ, 2-layer sandwich domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, GTPase domain superfamily
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Chem-S40 / Stathmin-4 / Stathmin-4 / Tubulin beta chain / Tubulin alpha-1B chain
Similarity search - Component
Biological speciesSus scrofa (pig)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsDu, T. / Lin, S. / Ji, M. / Xue, N. / Liu, Y. / Zhang, K. / Lu, D. / Chen, X. / Xu, H.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018ZX09711-001 China
CitationJournal: Cancer Lett. / Year: 2020
Title: A novel orally active microtubule destabilizing agent S-40 targets the colchicine-binding site and shows potent antitumor activity.
Authors: Du, T. / Lin, S. / Ji, M. / Xue, N. / Liu, Y. / Zhang, Z. / Zhang, K. / Zhang, J. / Zhang, Y. / Wang, Q. / Sheng, L. / Li, Y. / Lu, D. / Chen, X. / Xu, H.
History
DepositionJan 17, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 29, 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

Downloads & links

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Assembly

Deposited unit
A: Tubulin alpha-1B chain
B: Tubulin beta chain
C: Tubulin alpha-1B chain
D: Tubulin beta chain
E: Stathmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,75819
Polymers218,4695
Non-polymers3,28914
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20060 Å2
ΔGint-145 kcal/mol
Surface area64190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.680, 102.200, 131.500
Angle α, β, γ (deg.)90.000, 107.420, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 3 types, 5 molecules ACBDE

#1: Protein Tubulin alpha-1B chain / Alpha-tubulin ubiquitous / Tubulin K-alpha-1 / Tubulin alpha-ubiquitous chain


Mass: 50204.445 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: Q2XVP4
#2: Protein Tubulin beta chain / Beta-tubulin


Mass: 49999.887 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: P02554
#3: Protein Stathmin /


Mass: 18060.414 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sus scrofa (pig) / Gene: LOC100739720, LOC100155126 / Production host: Escherichia coli (E. coli) / References: UniProt: F2Z508, UniProt: A0A287AC62*PLUS

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Non-polymers , 7 types, 34 molecules

#4: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE / Guanosine triphosphate


Mass: 523.180 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#7: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID / MES (buffer)


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Chemical ChemComp-S40 / 3-[(4-cyclopropylphenyl)sulfonylamino]-4-methyl-N-(pyridin-3-ylmethyl)benzamide


Mass: 421.512 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C23H23N3O3S / Feature type: SUBJECT OF INVESTIGATION
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.43 Å3/Da / Density % sol: 49.31 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 6% PEG 4000, 6% GLYCEROL, 30mM MAGNESIUM CHLORIDE, 30mM CALCIUM CHLORIDE, 3.3% Jeffamin M-600, 100mM MES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 23, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 2.4→78.15 Å / Num. obs: 81134 / % possible obs: 99.3 % / Redundancy: 3.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.026 / Rrim(I) all: 0.049 / Net I/σ(I): 15.3 / Num. measured all: 276833 / Scaling rejects: 14
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.4-2.463.60.5622119859710.9270.3480.662299.3
10.73-78.1530.0228609490.9990.0130.02442.197.4

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
Aimless0.7.2data scaling
PDB_EXTRACT3.25data extraction
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JCB

5jcb


Resolution: 2.4→62.734 Å / SU ML: 0.31 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.23 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2401 3911 4.84 %
Rwork0.2221 76828 -
obs0.223 80739 98.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 138.88 Å2 / Biso mean: 82.0407 Å2 / Biso min: 46.85 Å2
Refinement stepCycle: final / Resolution: 2.4→62.734 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14174 0 208 20 14402
Biso mean--73.69 75.49 -
Num. residues----1843
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4-2.42930.3581440.3697274599
2.4293-2.460.42551240.361267998
2.46-2.49240.37631340.3537275599
2.4924-2.52650.37771500.3388271099
2.5265-2.56260.35781580.322272099
2.5626-2.60090.34411240.3094270498
2.6009-2.64150.37841230.3108274999
2.6415-2.68480.3371280.3107275999
2.6848-2.73110.32581350.3009273299
2.7311-2.78080.32151350.284273599
2.7808-2.83430.3061320.2561274199
2.8343-2.89210.30431310.2441275399
2.8921-2.9550.27961390.2428270999
2.955-3.02380.25961370.2396276999
3.0238-3.09940.26191500.258271199
3.0994-3.18320.30631500.25422781100
3.1832-3.27680.30051400.255274699
3.2768-3.38260.24591460.2437275199
3.3826-3.50350.2711450.2283273899
3.5035-3.64370.28471230.2248278499
3.6437-3.80960.24851290.2263275999
3.8096-4.01040.22031450.2133272799
4.0104-4.26160.25361660.2036273699
4.2616-4.59050.19381530.1822273799
4.5905-5.05230.17851520.1844274999
5.0523-5.7830.21691370.2141277599
5.783-7.28420.23851360.2217276998
7.2842-62.7340.16991450.1713280598

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