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- PDB-7dp8: Crystal structure of T2R-TTL-Cevipabulin-eribulin complex -

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Basic information

Entry
Database: PDB / ID: 7dp8
TitleCrystal structure of T2R-TTL-Cevipabulin-eribulin complex
Components
  • Stathmin-4
  • Tubulin alpha-1B chain
  • Tubulin beta chain
  • Tubulin tyrosine ligase
KeywordsSTRUCTURAL PROTEIN / tubulin inhibitor / tublin
Function / homology
Function and homology information


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 ...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 / nucleotide binding / GTPase activity / GTP binding / Golgi apparatus / metal ion binding / cytoplasm
Similarity search - Function
Rossmann fold - #11480 / 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. ...Rossmann fold - #11480 / 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. / ATP-grasp fold, B domain / D-amino Acid Aminotransferase; Chain A, domain 1 / 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 / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-6K9 / PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER / Chem-G2X / GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Tubulin beta chain / Tubulin tyrosine ligase / 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 / molecular replacement / Resolution: 2.446 Å
AuthorsChen, L.J. / Chen, Q. / Yu, Y. / Yang, J.H.
CitationJournal: Sci Adv / Year: 2021
Title: Cevipabulin-tubulin complex reveals a novel agent binding site on alpha-tubulin with tubulin degradation effect.
Authors: Yang, J. / Yu, Y. / Li, Y. / Yan, W. / Ye, H. / Niu, L. / Tang, M. / Wang, Z. / Yang, Z. / Pei, H. / Wei, H. / Zhao, M. / Wen, J. / Yang, L. / Ouyang, L. / Wei, Y. / Chen, Q. / Li, W. / Chen, L.
History
DepositionDec 18, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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-4
F: Tubulin tyrosine ligase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)266,22428
Polymers261,3056
Non-polymers4,91922
Water2,126118
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area24930 Å2
ΔGint-175 kcal/mol
Surface area79860 Å2
Unit cell
Length a, b, c (Å)103.937, 159.071, 176.236
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 4 types, 6 molecules ACBDEF

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


Mass: 50041.273 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: 49999.887 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A287AGU7
#3: Protein Stathmin-4 / Stathmin-like protein B3 / RB3


Mass: 16844.162 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: 44378.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: TTL / Production host: Escherichia coli (E. coli) / References: UniProt: E1BQ43

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Non-polymers , 10 types, 140 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.: 5 / Source method: obtained synthetically / Formula: Mg
#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#9: 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
#10: 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
#11: Chemical ChemComp-G2X / 6-[2,6-bis(fluoranyl)-4-[3-(methylamino)propoxy]phenyl]-5-chloranyl-N-[(2S)-1,1,1-tris(fluoranyl)propan-2-yl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine


Mass: 464.820 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H18ClF5N6O / Feature type: SUBJECT OF INVESTIGATION
#12: Chemical ChemComp-6K9 / (1S,3S,6S,9S,12S,14R,16R,18S,20R,21R,22S,26R,29S,31R,32S,33R,35R,36S)-20-[(2S)-3-amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-dimethylidene-2,19,30,34,37,39,40,41-octaoxanonacyclo[24.9.2.1~3,32~.1~3,33~.1~6,9~.1~12,16~.0~18,22~.0~29,36~.0~31,35~]hentetracontan-24-one (non-preferred name)


Mass: 729.897 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H59NO11
#13: 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
#14: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 2.79 Å3/Da / Density % sol: 55.88 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 6% poly(ethylene glycol) 4000, 8% glycerol, 0.1 M MES (pH 6.7), 30 mM CaCl2 and 30 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97855 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97855 Å / Relative weight: 1
ReflectionResolution: 2.446→60 Å / Num. obs: 102989 / % possible obs: 95.1 % / Redundancy: 12.9 % / CC1/2: 0.99 / Rpim(I) all: 0.027 / Net I/σ(I): 15
Reflection shellResolution: 2.446→2.489 Å / Num. unique obs: 5328 / CC1/2: 0.763 / Rpim(I) all: 0.371

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.15.2_3472refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5JH7

5jh7


Resolution: 2.446→59.46 Å / SU ML: 0.29 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.17 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2637 5151 5.01 %
Rwork0.2268 97726 -
obs0.2287 102877 95.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 313.16 Å2 / Biso mean: 68.9958 Å2 / Biso min: 26.04 Å2
Refinement stepCycle: final / Resolution: 2.446→59.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17367 0 422 118 17907
Biso mean--67.32 54.48 -
Num. residues----2196
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4464-2.47420.3261650.30793392100
2.4742-2.50330.3611770.30273365100
2.5033-2.53380.30941870.29883413100
2.5338-2.56590.32981850.30293370100
2.5659-2.59970.30611780.30293398100
2.5997-2.63530.31951810.30763366100
2.6353-2.67290.3617520.3533122595
2.6729-2.71280.3916310.31757955
2.7128-2.75520.31451670.28983440100
2.7552-2.80040.35361720.28393406100
2.8004-2.84870.3122110.28083333100
2.8487-2.90050.31451710.28193407100
2.9005-2.95630.36031760.27993417100
2.9563-3.01660.31441640.2783417100
3.0166-3.08220.31381730.28693399100
3.0822-3.15390.31511790.28413439100
3.1539-3.23280.31111640.28183399100
3.2328-3.32020.31271710.26463450100
3.3202-3.41790.27372040.27233351100
3.4179-3.52820.28811870.2599341299
3.5282-3.65420.26632090.23833386100
3.6542-3.80050.2981810.23093428100
3.8005-3.97350.25291740.22340299
3.9735-4.18290.23391850.19653453100
4.1829-4.44490.23511820.18153438100
4.4449-4.7880.21661740.17383473100
4.788-5.26950.21331780.18273483100
5.2695-6.03140.25881950.20553484100
6.0314-7.59640.24222050.20593522100
7.5964-59.460.19241730.1743367999

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