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PDBsum entry 4o2b
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Cell cycle/inhibitor
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PDB id
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4o2b
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Contents |
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439 a.a.
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422 a.a.
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121 a.a.
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319 a.a.
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PDB id:
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| Name: |
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Cell cycle/inhibitor
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Title:
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Tubulin-colchicine complex
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Structure:
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Tubulin alpha-1b chain. Chain: a, c. Synonym: alpha-tubulin ubiquitous, tubulin k-alpha-1, tubulin alpha- ubiquitous chain. Tubulin beta-2b chain. Chain: b, d. Stathmin-4. Chain: e. Synonym: stathmin-like protein b3, rb3.
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Source:
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Bos taurus. Bovine. Organism_taxid: 9913. Other_details: brain. Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: stmn4. Expressed in: escherichia coli.
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Resolution:
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2.30Å
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R-factor:
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0.183
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R-free:
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0.213
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Authors:
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A.E.Prota,D.Franck,F.Bachmann,K.Bargsten,R.M.Buey,J.Pohlmann, S.Reinelt,H.Lane,M.O.Steinmetz
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Key ref:
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A.E.Prota
et al.
(2014).
The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization.
J Mol Biol,
426,
1848-1860.
PubMed id:
DOI:
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Date:
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17-Dec-13
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Release date:
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05-Mar-14
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PROCHECK
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Headers
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References
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P81947
(TBA1B_BOVIN) -
Tubulin alpha-1B chain from Bos taurus
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Seq:
Struc:
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451 a.a.
439 a.a.
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Q6B856
(TBB2B_BOVIN) -
Tubulin beta-2B chain from Bos taurus
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Seq:
Struc:
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445 a.a.
422 a.a.
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DOI no:
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J Mol Biol
426:1848-1860
(2014)
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PubMed id:
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The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization.
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A.E.Prota,
F.Danel,
F.Bachmann,
K.Bargsten,
R.M.Buey,
J.Pohlmann,
S.Reinelt,
H.Lane,
M.O.Steinmetz.
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ABSTRACT
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Microtubule-targeting agents are widely used for the treatment of cancer and as
tool compounds to study the microtubule cytoskeleton. BAL27862 is a novel
microtubule-destabilizing drug that is currently undergoing phase I clinical
evaluation as the prodrug BAL101553. The drug is a potent inhibitor of tumor
cell growth and shows a promising activity profile in a panel of human cancer
models resistant to clinically relevant microtubule-targeting agents. Here, we
evaluated the molecular mechanism of the tubulin-BAL27862 interaction using a
combination of cell biology, biochemistry and structural biology methods.
Tubulin-binding assays revealed that BAL27862 potently inhibited tubulin
assembly at 37°C with an IC50 of 1.4μM and bound to unassembled tubulin with a
stoichiometry of 1mol/mol tubulin and a dissociation constant of 244±30nM.
BAL27862 bound to tubulin independently of vinblastine, without the formation of
tubulin oligomers. The kinetics of BAL27862 binding to tubulin were distinct
from those of colchicine, with evidence of competition between BAL27862 and
colchicine for binding. Determination of the tubulin-BAL27862 structure by X-ray
crystallography demonstrated that BAL27862 binds to the same site as colchicine
at the intradimer interface. Comparison of crystal structures of
tubulin-BAL27862 and tubulin-colchicine complexes shows that the binding mode of
BAL27862 to tubulin is similar to that of colchicine. However, comparative
analyses of the effects of BAL27862 and colchicine on the microtubule mitotic
spindle and in tubulin protease-protection experiments suggest different
outcomes of tubulin binding. Taken together, our data define BAL27862 as a
potent, colchicine site-binding, microtubule-destabilizing agent with distinct
effects on microtubule organization.
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