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- PDB-4x1i: Discovery of cytotoxic Dolastatin 10 analogs with N-terminal modi... -

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Basic information

Entry
Database: PDB / ID: 4x1i
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 / microtubule polymerization / locomotory exploration behavior / regulation of microtubule polymerization or depolymerization / response to mechanical stimulus / sperm flagellum / 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 / recycling endosome / cerebral cortex development / synapse organization / visual learning / structural constituent of cytoskeleton / memory / neuron migration / cytoplasmic ribonucleoprotein granule / neuron projection development / growth cone / neuron apoptotic process / gene expression / microtubule / neuron projection / hydrolase activity / protein heterodimerization activity / GTPase activity / GTP binding / protein-containing complex binding / Golgi apparatus / metal ion binding / identical protein binding / plasma membrane / cytosol / cytoplasm
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
2-methyl-L-alanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide / Chem-3WD / 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: 3.11 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 24, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 8, 2015Group: Non-polymer description
Revision 1.2Nov 22, 2017Group: Derived calculations / Refinement description / Source and taxonomy
Category: entity_src_gen / entity_src_nat ...entity_src_gen / entity_src_nat / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _entity_src_nat.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Sep 27, 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 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)221,30315
Polymers217,0365
Non-polymers4,26610
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18090 Å2
ΔGint-105 kcal/mol
Surface area66130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.140, 128.210, 255.140
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-3WD / 2-methyl-L-alanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 743.011 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H62N6O6S
References: 2-methyl-L-alanyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-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: 2.61 Å3/Da / Density % sol: 52.87 %
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: 3.1→50 Å / Num. obs: 40139 / % possible obs: 99.9 % / Redundancy: 6.4 % / Biso Wilson estimate: 91.3 Å2 / Rmerge(I) obs: 0.106 / Χ2: 1.036 / Net I/av σ(I): 16.219 / Net I/σ(I): 5.3 / Num. measured all: 258475
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Num. unique allΧ2% possible allRmerge(I) obs
3.1-3.156.319970.79999.7
3.15-3.216.419460.806100
3.21-3.276.419940.79100
3.27-3.346.419770.7961000.853
3.34-3.416.619530.80799.90.742
3.41-3.496.519900.8291000.581
3.49-3.586.619620.8261000.452
3.58-3.686.519990.8891000.366
3.68-3.786.519660.8521000.305
3.78-3.916.120030.9091000.268
3.91-4.046.119740.921000.195
4.04-4.216.619890.9911000.155
4.21-4.46.220261.0741000.118
4.4-4.636.519911.1891000.096
4.63-4.926.920041.2271000.089
4.92-5.36.820151.1441000.087
5.3-5.836.720401.1441000.088
5.83-6.676.420571.1851000.074
6.67-8.4620761.4551000.052
8.4-506.221801.99598.80.042

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Processing

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

3hkb


Resolution: 3.11→45.3 Å / Cor.coef. Fo:Fc: 0.9277 / Cor.coef. Fo:Fc free: 0.8835 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.467
RfactorNum. reflection% reflectionSelection details
Rfree0.2529 1998 5 %RANDOM
Rwork0.1908 ---
obs0.194 39936 99.92 %-
Displacement parametersBiso mean: 119.23 Å2
Baniso -1Baniso -2Baniso -3
1--44.3366 Å20 Å20 Å2
2--18.2857 Å20 Å2
3---26.0509 Å2
Refine analyzeLuzzati coordinate error obs: 0.785 Å
Refinement stepCycle: LAST / Resolution: 3.11→45.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14448 0 284 0 14732
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00915018HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0920372HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5234SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes401HARMONIC2
X-RAY DIFFRACTIONt_gen_planes2298HARMONIC5
X-RAY DIFFRACTIONt_it15018HARMONIC20
X-RAY DIFFRACTIONt_nbd67SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.25
X-RAY DIFFRACTIONt_other_torsion22.74
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1950SEMIHARMONIC5
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_contact17571SEMIHARMONIC4
LS refinement shellResolution: 3.11→3.19 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3502 141 4.85 %
Rwork0.257 2767 -
all0.2614 2908 -
obs--99.92 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3157-0.3697-0.08543.63250.81331.659-0.29490.1246-0.03060.02880.5456-0.43980.49390.1413-0.25070.5811-0.02170.2167-0.3677-0.2895-0.387210.767533.47875.0083
21.0569-0.82610.22643.98980.68650.9679-0.18470.19960.0921-0.03150.3315-0.48860.22380.141-0.14680.2630.1039-0.0188-0.183-0.1665-0.34674.675771.008492.05
31.6554-1.1599-0.2593.7411.41971.4960.06560.03410.1794-0.17290.2015-0.33280.17770.3643-0.26710.02540.0924-0.0255-0.1652-0.1361-0.2534-9.1418110.48106.033
42.3809-0.7140.24782.80390.69962.2090.06520.19140.34-0.2676-0.17480.10290.13320.05680.1096-0.2444-0.02890.0102-0.1116-0.0725-0.0065-30.4437144.381119.136
50.2529-0.6985-0.45881.96780.94810.4663-0.0646-0.07490.0128-0.11670.0470.13510.2-0.26530.01760.2837-0.1278-0.0769-0.1866-0.247-0.055-24.590378.979189.0305
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }

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