title: Terpendole E and its derivative inhibit STLC- and GSK-1-resistant Eg5.
abstract: 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.
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572 (Japan).
authors.forename: Yuka
authors.initials: Y
authors.lastname: Tarui
authors.forename: Takumi
authors.initials: T
authors.lastname: Chinen
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagumo
authors.forename: Takayuki
authors.initials: T
authors.lastname: Motoyama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirota
authors.forename: Makoto
authors.initials: M
authors.lastname: Muroi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Hisae
authors.initials: H
authors.lastname: Kondo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015180:Electrophoresis, Gel, Two-Dimensional; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D016296:Mutagenesis; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020543:Proteome / Q000032:analysis
chemical_list: C000594500:11-ketopaspaline; D004224:Diterpenes; D007211:Indoles; C470243:KIF11 protein, human; D009842:Oligopeptides; D020543:Proteome; C477863:terpendole E; C003724:3-tritylthio-L-alanine; C056289:GSK peptide; D016547:Kinesins; D003545:Cysteine
keywords: ATPase activity; inhibitors; microtubules; noncovalent interactions; terpendole E