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- PDB-4x1y: Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modi... -

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Basic information

Entry
Database: PDB / ID: 4x1y
TitleDiscovery of cytotoxic Dolastatin 10 analogs with N-terminal modifications
Components
  • Stathmin-4
  • Tubulin alpha chain
  • Tubulin beta chain
KeywordsStructural Protein/Inhibitor / Binding Sites / Competitive / Cattle / Tumor / Colchicine / Humans / Microtubules / Protein Binding / Protein Conformation / Protein Multimerization / Tubulin / Tubulin Modulators / Structural Protein-Inhibitor complex
Function / homology
Function and homology information


axonemal microtubule / organelle transport along microtubule / forebrain morphogenesis / cerebellar cortex morphogenesis / glial cell differentiation / dentate gyrus development / neuron projection arborization / flagellated sperm motility / response to L-glutamate / pyramidal neuron differentiation ...axonemal microtubule / organelle transport along microtubule / forebrain morphogenesis / cerebellar cortex morphogenesis / glial cell differentiation / dentate gyrus development / neuron projection arborization / flagellated sperm motility / response to L-glutamate / pyramidal neuron differentiation / microtubule depolymerization / centrosome cycle / smoothened signaling pathway / regulation of synapse organization / startle response / motor behavior / response to tumor necrosis factor / locomotory exploration behavior / microtubule polymerization / regulation of microtubule polymerization or depolymerization / sperm flagellum / response to mechanical stimulus / microtubule-based process / condensed chromosome / homeostasis of number of cells within a tissue / tubulin binding / cellular response to calcium ion / adult locomotory behavior / neuromuscular junction / intracellular protein transport / synapse organization / recycling endosome / cerebral cortex development / visual learning / structural constituent of cytoskeleton / memory / cytoplasmic ribonucleoprotein granule / neuron migration / neuron projection development / growth cone / neuron apoptotic process / gene expression / microtubule / hydrolase activity / neuron projection / protein heterodimerization activity / GTPase activity / GTP binding / protein-containing complex binding / Golgi apparatus / metal ion binding / identical protein binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #30 / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Helix hairpin bin / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #30 / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Helix hairpin bin / Stathmin family / Stathmin, conserved site / Stathmin superfamily / Stathmin family / Stathmin family signature 1. / Stathmin family signature 2. / Stathmin-like (SLD) domain profile. / Tubulin/FtsZ, C-terminal domain / Tubulin/FtsZ, GTPase domain / 60s Ribosomal Protein L30; Chain: A; / 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 / Helix non-globular / Special / Helix Hairpins / Rossmann fold / 2-Layer Sandwich / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
N,2-dimethyl-L-alanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide / Chem-3WV / GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Chem-LOC / Tubulin beta chain / Tubulin alpha chain / Stathmin-4
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Ovis aries (sheep)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.19 Å
AuthorsParris, K.D.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.
Authors: Maderna, A. / Doroski, M. / Subramanyam, C. / Porte, A. / Leverett, C.A. / Vetelino, B.C. / Chen, Z. / Risley, H. / Parris, K. / Pandit, J. / Varghese, A.H. / Shanker, S. / Song, C. / ...Authors: Maderna, A. / Doroski, M. / Subramanyam, C. / Porte, A. / Leverett, C.A. / Vetelino, B.C. / Chen, Z. / Risley, H. / Parris, K. / Pandit, J. / Varghese, A.H. / Shanker, S. / Song, C. / Sukuru, S.C. / Farley, K.A. / Wagenaar, M.M. / Shapiro, M.J. / Musto, S. / Lam, M.H. / Loganzo, F. / O'Donnell, C.J.
History
DepositionNov 25, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Non-polymer description
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / entity_src_nat / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _entity_src_nat.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tubulin alpha chain
B: Tubulin beta chain
C: Tubulin alpha chain
D: Tubulin beta chain
E: Stathmin-4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)221,25315
Polymers217,0365
Non-polymers4,21610
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18040 Å2
ΔGint-104 kcal/mol
Surface area65940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.610, 127.860, 255.040
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 3 types, 5 molecules ACBDE

#1: Protein Tubulin alpha chain


Mass: 50188.441 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) / References: UniProt: D0VWZ0
#2: Protein Tubulin beta chain


Mass: 49969.797 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep) / References: UniProt: D0VWY9
#3: Protein Stathmin-4 / Stathmin-like protein B3 / RB3


Mass: 16719.938 Da / Num. of mol.: 1 / Fragment: UNP residues 49-189
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

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Non-polymers , 5 types, 10 molecules

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


Mass: 523.180 Da / Num. of mol.: 2 / 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.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#7: Chemical ChemComp-LOC / N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[d]heptalen-7-yl]ethanamide / COLCHICINE


Mass: 399.437 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H25NO6
#8: Chemical ChemComp-3WV / N,2-dimethyl-L-alanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 717.936 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H63N5O8
References: N,2-dimethyl-L-alanyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide

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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: 2.62 Å3/Da / Density % sol: 53.05 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 5% PEG 400, 0.1M LiSO4, 5-7% PEG 20K, 50 mM K-PIPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 9, 2012
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.19→50 Å / Num. obs: 36225 / % possible obs: 97.5 % / Redundancy: 4.5 % / Biso Wilson estimate: 94.19 Å2 / Rmerge(I) obs: 0.104 / Χ2: 0.842 / Net I/av σ(I): 14.559 / Net I/σ(I): 4.7 / Num. measured all: 164538
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
3.19-3.263.70.83216420.50490.4
3.26-3.313.80.65817290.46394.4
3.31-3.383.90.60717400.47595.6
3.38-3.453.90.54117950.4998.6
3.45-3.524.40.46518130.50298.6
3.52-3.64.50.36417840.51898.5
3.6-3.694.60.32418360.51498.7
3.69-3.794.90.28117880.53398.8
3.79-3.914.90.25318290.55198.6
3.91-4.034.90.19917980.58798.7
4.03-4.184.90.15518370.65798.9
4.18-4.344.80.12617890.71798.6
4.34-4.544.50.11118380.90698.4
4.54-4.784.80.09818330.93697.9
4.78-5.084.80.0918160.9498.3
5.08-5.4750.09518200.93598.3
5.47-6.024.80.09418640.92498
6.02-6.894.50.08518491.05697.9
6.89-8.674.70.07718681.58397.2
8.67-504.40.06819572.63695.1

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
DENZOdata reduction
PDB_EXTRACT3.15data extraction
SCALEPACKdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HKB

3hkb


Resolution: 3.19→30.59 Å / Cor.coef. Fo:Fc: 0.9218 / Cor.coef. Fo:Fc free: 0.8849 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.548
RfactorNum. reflection% reflectionSelection details
Rfree0.2731 1817 5.03 %RANDOM
Rwork0.1883 ---
obs0.1926 36145 97.25 %-
Displacement parametersBiso mean: 126.67 Å2
Baniso -1Baniso -2Baniso -3
1--58.7925 Å20 Å20 Å2
2--31.0092 Å20 Å2
3---27.7833 Å2
Refine analyzeLuzzati coordinate error obs: 0.737 Å
Refinement stepCycle: LAST / Resolution: 3.19→30.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14445 0 282 0 14727
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0115010HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.2220359HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5233SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes401HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2286HARMONIC5
X-RAY DIFFRACTIONt_it15010HARMONIC20
X-RAY DIFFRACTIONt_nbd67SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.57
X-RAY DIFFRACTIONt_other_torsion24.44
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1949SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact18146SEMIHARMONIC4
LS refinement shellResolution: 3.19→3.28 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2942 124 4.69 %
Rwork0.2448 2520 -
all0.2471 2644 -
obs--97.25 %

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