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PDBsum entry 5lp6
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Structural protein
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PDB id
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5lp6
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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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340 a.a.
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PDB id:
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| Name: |
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Structural protein
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Title:
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Crystal structure of tubulin-stathmin-ttl-thiocolchicine 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. Rattus norvegicus. Rat. Organism_taxid: 10116. Gene: stmn4. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.90Å
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R-factor:
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0.274
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R-free:
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0.305
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Authors:
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J.Marangon,M.Christodoulou,F.Casagrande,G.Tiana,L.Dalla Via, A.Aliverti,D.Passarella,G.Cappelletti,S.Ricagno
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Key ref:
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J.Marangon
et al.
(2016).
Tools for the rational design of bivalent microtubule-targeting drugs.
Biochem Biophys Res Commun,
479,
48-53.
PubMed id:
DOI:
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Date:
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11-Aug-16
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Release date:
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21-Sep-16
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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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Biochem Biophys Res Commun
479:48-53
(2016)
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PubMed id:
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Tools for the rational design of bivalent microtubule-targeting drugs.
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J.Marangon,
M.S.Christodoulou,
F.V.Casagrande,
G.Tiana,
L.Dalla Via,
A.Aliverti,
D.Passarella,
G.Cappelletti,
S.Ricagno.
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ABSTRACT
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Microtubule (MT) dynamic behaviour is an attractive drug target for
chemotherapy, whose regulation by MT-stabilizing and destabilizing agents has
been fruitfully applied in treating several types of cancers. MT-stabilizing
agents are also emerging as potential remedies for neurodegenerative conditions,
such as Alzheimer's and Parkinson's disease, although single-target drugs are
not expected to fully cure these complex pathologies. Drug combination often
displays enhanced efficacy with respect to mono-therapies. In particular,
MT-targeting bivalent compounds (MTBCs) represent a promising class of
molecules; however, surprisingly, the majority of MTBCs reported so far exhibit
equal if not less efficacy than their building monomers. In order to shed light
on MTBCs poor performance, we characterised through a set of complementary
approaches thiocolchine (TH) and two bivalent TH-homodimers as prototype
molecules. First, the binding affinities of these three molecules were assessed,
then we obtained the crystallographic structure of a tubulin-TH complex. The
binding affinities were interpreted in light of structural data and of molecular
dynamics simulations. Finally, their effects on MT cytoskeleton and cell
survival were validated on HeLa cells. The ensemble of these data provides
chemical and structural considerations on how a successful rational design of
MTBCs should be conceived.
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