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Terpendole E and its Derivative Inhibit STLC‐ and GSK‐1‐Resistant Eg5
Author(s) -
Tarui Yuka,
Chinen Takumi,
Nagumo Yoko,
Motoyama Takayuki,
Hayashi Toshiaki,
Hirota Hiroshi,
Muroi Makoto,
Ishii Yasuyuki,
Kondo Hisae,
Osada Hiroyuki,
Usui Takeo
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201300808
Subject(s) - natural product , microtubule , kinesin , chemistry , mutant , inhibitory postsynaptic potential , binding site , microbiology and biotechnology , biochemistry , biology , gene , neuroscience
Terpendole E is first natural product found to inhibit mitotic kinesin Eg5, but its inhibitory mechanism remains to be revealed. Here, we report the effects of terpendole E and 11ketopaspaline (a new natural terpendole E analogue) on the Eg5–microtubule interaction and in several Eg5 mutants. 11‐Ketopaspaline is a shunt product from terpendole E, and it shows potent inhibitory activity against the microtubule‐stimulated ATPase activity of Eg5. Unlike other Eg5 inhibitors, such as S ‐trityl‐ L ‐cysteine (STLC) and GSK‐1, both terpendole E and 11‐ketopaspaline only partially inhibited Eg5–microtubule interaction. Furthermore, terpendole E and 11‐ketopaspaline inhibited several Eg5 mutants that are resistant to STLC (Eg5 D130A , Eg5 L214A ) or GSK‐1 (Eg5 I299F , Eg5 A356T ), but with the same extent of inhibition against wild‐type Eg5. Because Eg5 D130A and Eg5 L214A show cross‐resistance to most known Eg5 inhibitors, which bind the L5 loop, these results suggest that terpendole E and its analogues have a different binding site and/or inhibitory mechanism to those for L5 loop‐binding type Eg5 inhibitors.