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- PDB-8wmu: Structural basis of tubulin and heterocyclic podophyllotoxins com... -

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Basic information

Entry
Database: PDB / ID: 8wmu
TitleStructural basis of tubulin and heterocyclic podophyllotoxins complex for anticancer agents with dual-binding sites
Components
  • Detyrosinated tubulin alpha-1B chain
  • Stathmin-4
  • Tubulin beta chain
  • Tubulin--tyrosine ligase
KeywordsCELL CYCLE / tublin / inhibitor / two binding sites
Function / homology
Function and homology information


tubulin-tyrosine ligase / tubulin-tyrosine ligase activity / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Resolution of Sister Chromatid Cohesion / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / Carboxyterminal post-translational modifications of tubulin ...tubulin-tyrosine ligase / tubulin-tyrosine ligase activity / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Resolution of Sister Chromatid Cohesion / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Mitotic Prometaphase / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / EML4 and NUDC in mitotic spindle formation / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins / PKR-mediated signaling / Separation of Sister Chromatids / The role of GTSE1 in G2/M progression after G2 checkpoint / Aggrephagy / microtubule depolymerization / RHO GTPases activate IQGAPs / RHO GTPases Activate Formins / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / COPI-mediated anterograde transport / regulation of microtubule polymerization or depolymerization / microtubule-based process / tubulin binding / spindle microtubule / protein modification process / structural constituent of cytoskeleton / microtubule cytoskeleton organization / neuron projection development / mitotic cell cycle / microtubule cytoskeleton / growth cone / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule / neuron projection / GTPase activity / GTP binding / Golgi apparatus / metal ion binding / cytoplasm
Similarity search - Function
: / Tubulin-tyrosine ligase/Tubulin polyglutamylase / Tubulin-tyrosine ligase family / TTL domain profile. / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. ...: / Tubulin-tyrosine ligase/Tubulin polyglutamylase / Tubulin-tyrosine ligase family / TTL domain profile. / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / 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
: / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / DI(HYDROXYETHYL)ETHER / Tubulin--tyrosine ligase / Tubulin beta chain / Stathmin-4 / Tubulin alpha-1B chain
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Gallus gallus (chicken)
Sus scrofa (pig)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsZhao, W. / Bi, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: To Be Published
Title: Structural basis of tubulin and heterocyclic podophyllotoxins complex for anticancer agents with dual-binding sites
Authors: Zhao, W.
History
DepositionOct 4, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Detyrosinated tubulin alpha-1B chain
B: Tubulin beta chain
C: Detyrosinated tubulin alpha-1B chain
D: Tubulin beta chain
E: Stathmin-4
F: Tubulin--tyrosine ligase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)258,49121
Polymers254,8246
Non-polymers3,66715
Water2,378132
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.572, 157.618, 179.348
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 1 or (resid 2 and (name...
d_2ens_1(chain "C" and (resid 1 through 34 or (resid 35...
d_1ens_2(chain "B" and ((resid 1 through 2 and (name N...
d_2ens_2(chain "D" and ((resid 1 through 2 and (name N...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1METMETVALVALAA1 - 4371 - 437
d_21ens_1METMETLYSLYSCC1 - 2801 - 280
d_22ens_1GLUGLUVALVALCC284 - 437284 - 437
d_11ens_2METMETLEULEUBB1 - 2731 - 273
d_12ens_2LEULEUALAALABB284 - 428284 - 428
d_21ens_2METMETGLUGLUDD1 - 531 - 53
d_22ens_2ASNASNALAALADD57 - 42857 - 428

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.947502595298, 0.248842421209, -0.200789146394), (-0.273081547316, 0.956426094831, -0.103322764389), (0.166328892314, 0.152730398194, 0.974170480485)-22.428024715, -63.8740929309, 54.7521555902
2given(0.9456902966, 0.237826906491, -0.221603757789), (-0.26420764202, 0.959498429735, -0.0977603459209), (0.189378416974, 0.151000416838, 0.970224040776)-22.8957062557, -63.7307287468, 55.1922170288

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Components

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Protein , 4 types, 6 molecules ACBDEF

#1: Protein Detyrosinated tubulin alpha-1B chain


Mass: 48966.324 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


Mass: 48391.410 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A8D0VN39
#3: Protein Stathmin-4 / Stathmin-like protein B3 / RB3


Mass: 16282.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Stmn4 / Production host: Escherichia coli (E. coli) / References: UniProt: P63043
#4: Protein Tubulin--tyrosine ligase


Mass: 43825.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Sequence reference for source organism Gallus gallus is not available in UniProt at the time of biocuration. Current sequence reference is from UniProt id A0A8C9FGJ1.
Source: (gene. exp.) Gallus gallus (chicken) / Production host: Escherichia coli (E. coli) / References: UniProt: A0A8C9FGJ1, tubulin-tyrosine ligase

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Non-polymers , 11 types, 147 molecules

#5: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


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


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#9: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#10: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


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


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#12: Chemical ChemComp-A1D55 / (5~{S},5~{a}~{S},8~{a}~{R},9~{R})-5-(quinolin-6-ylamino)-9-(3,4,5-trimethoxyphenyl)-5~{a},6,8~{a},9-tetrahydro-5~{H}-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one


Mass: 540.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H28N2O7 / Feature type: SUBJECT OF INVESTIGATION
#13: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#14: Chemical ChemComp-ACP / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / ADENOSINE-5'-[BETA, GAMMA-METHYLENE]TRIPHOSPHATE


Mass: 505.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H18N5O12P3 / Comment: AMP-PCP, energy-carrying molecule analogue*YM
#15: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.98 Å3/Da / Density % sol: 58.71 %
Crystal growTemperature: 277 K / Method: vapor diffusion
Details: 6% PEG4000, 6% glycerol, 30 mM MgCl2, 30 mM CaCl2, 100 mM MES-Na

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 7, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 80188 / % possible obs: 97.73 % / Redundancy: 6.7 % / Biso Wilson estimate: 39.92 Å2 / CC1/2: 0.9 / Net I/σ(I): 39.91
Reflection shellResolution: 2.7→2.796 Å / Num. unique obs: 7102 / CC1/2: 0.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→47.83 Å / SU ML: 0.2991 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 24.1084
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2454 4014 5.01 %
Rwork0.1972 76138 -
obs0.1996 80152 97.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 45.01 Å2
Refinement stepCycle: LAST / Resolution: 2.7→47.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16809 0 229 132 17170
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008917408
X-RAY DIFFRACTIONf_angle_d1.064723622
X-RAY DIFFRACTIONf_chiral_restr0.05922593
X-RAY DIFFRACTIONf_plane_restr0.00833046
X-RAY DIFFRACTIONf_dihedral_angle_d18.8416337
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.38275263466
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.959036193822
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7-2.730.33751110.26292147X-RAY DIFFRACTION81.49
2.73-2.760.33861260.2652328X-RAY DIFFRACTION87.77
2.76-2.80.29781260.24092542X-RAY DIFFRACTION96.11
2.8-2.840.32181600.24382558X-RAY DIFFRACTION96.28
2.84-2.880.28871510.24482607X-RAY DIFFRACTION99.14
2.88-2.920.33021340.23242621X-RAY DIFFRACTION98.22
2.92-2.960.29671420.23152641X-RAY DIFFRACTION99.82
2.96-3.010.25691210.22482642X-RAY DIFFRACTION98.57
3.01-3.060.3141250.23182660X-RAY DIFFRACTION99.68
3.06-3.110.32121520.22922603X-RAY DIFFRACTION98.04
3.11-3.160.2751410.22752547X-RAY DIFFRACTION96.21
3.16-3.230.27221170.22922673X-RAY DIFFRACTION99.75
3.23-3.290.31281470.22162629X-RAY DIFFRACTION98.79
3.29-3.360.28721520.21142656X-RAY DIFFRACTION99.61
3.36-3.440.24361440.20792658X-RAY DIFFRACTION99.47
3.44-3.530.24431270.20022652X-RAY DIFFRACTION99
3.53-3.620.24511390.19042648X-RAY DIFFRACTION99.32
3.62-3.730.22111310.19532694X-RAY DIFFRACTION99.61
3.73-3.850.20511430.18852660X-RAY DIFFRACTION99.68
3.85-3.990.21341370.18442655X-RAY DIFFRACTION99.36
3.99-4.150.24291570.17392601X-RAY DIFFRACTION97.22
4.15-4.340.21461410.17392679X-RAY DIFFRACTION99.54
4.34-4.560.22581470.15732675X-RAY DIFFRACTION99.44
4.56-4.850.18691330.15652702X-RAY DIFFRACTION99.61
4.85-5.220.21531370.17192722X-RAY DIFFRACTION99.72
5.22-5.750.23831470.19922699X-RAY DIFFRACTION99.72
5.75-6.580.27141560.21362676X-RAY DIFFRACTION97.93
6.58-8.280.22321340.18812775X-RAY DIFFRACTION99.62
8.28-47.830.17671360.17442788X-RAY DIFFRACTION95.71
Refinement TLS params.Method: refined / Origin x: -17.6198494323 Å / Origin y: 43.9798213656 Å / Origin z: -26.0006761424 Å
111213212223313233
T0.13523920477 Å2-0.0302715726855 Å20.00877729028915 Å2-0.235150858594 Å20.0150325941988 Å2--0.301211403711 Å2
L0.225868305029 °2-0.0067978266658 °2-0.0516590806717 °2-0.739949134133 °2-0.721097410086 °2--1.20209164647 °2
S-0.0360914873148 Å °0.0267277223915 Å °0.0151765791824 Å °-0.0862686850236 Å °0.0648233010556 Å °-0.016689464622 Å °0.0620096172004 Å °-0.0119159154394 Å °-0.0274367442148 Å °
Refinement TLS groupSelection details: all

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