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PDBsum entry 5xp3
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Structural protein
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PDB id
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5xp3
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Contents |
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437 a.a.
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428 a.a.
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121 a.a.
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334 a.a.
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References listed in PDB file
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Key reference
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Title
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The compound millepachine and its derivatives inhibit tubulin polymerization by irreversibly binding to the colchicine-Binding site in β-Tubulin.
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Authors
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J.Yang,
W.Yan,
Y.Yu,
Y.Wang,
T.Yang,
L.Xue,
X.Yuan,
C.Long,
Z.Liu,
X.Chen,
M.Hu,
L.Zheng,
Q.Qiu,
H.Pei,
D.Li,
F.Wang,
P.Bai,
J.Wen,
H.Ye,
L.Chen.
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Ref.
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J Biol Chem, 2018,
293,
9461-9472.
[DOI no: ]
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PubMed id
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Abstract
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Inhibitors that bind to the paclitaxel- or vinblastine-binding sites of tubulin
have been part of the pharmacopoeia of anticancer therapy for decades. However,
tubulin inhibitors that bind to the colchicine-binding site are not used in
clinical cancer therapy, because of their low therapeutic index. To address
multidrug resistance to many conventional tubulin-binding agents, numerous
efforts have attempted to clinically develop inhibitors that bind the
colchicine-binding site. Previously, we have found that millepachine (MIL), a
natural chalcone-type small molecule extracted from the plant Millettia
pachycarpa, and its two derivatives (MDs) SKLB028 and SKLB050 have potential
antitumor activities both in vitro and in vivo However, their
cellular targets and mechanisms are unclear. Here, biochemical and cellular
experiments revealed that the MDs directly and irreversibly bind β-tubulin.
X-ray crystallography of the tubulin-MD structures disclosed that the MDs bind
at the tubulin intradimer interface and to the same site as colchicine and that
their binding mode is similar to that of colchicine. Of note, MDs inhibited
tubulin polymerization and caused G2/M cell-cycle arrest.
Comprehensive analysis further revealed that free MIL exhibits an s-cis
conformation, whereas MIL in the colchicine-binding site in tubulin adopts an
s-trans conformation. Moreover, introducing an α-methyl to MDs to
increase the proportion of s-trans conformations augmented MDs' tubulin
inhibition activity. Our study uncovers a new class of chalcone-type tubulin
inhibitors that bind the colchicine-binding site in β-tubulin and suggests that
the s-trans conformation of these compounds may make them more active
anticancer agents.
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