Structure basis for antitumor effect of aplyronine a.
Aplyronine A, isolated from the sea hare Aplysia kurodai, possesses an exceedingly potent antitumor effect in vivo and it is one of the promising candidates as an anticancer drug. This macrolide is known to depolymerize F-actin and inhibit the polymerization of actin by forming a 1:1 complex with monomeric actin. The first complex structure of actin-aplyronine A was determined via a synchrotron X-ray analysis at a 1.45 A resolution. As expected, aplyronine A binds to a hydrophobic cleft composed of subdomains 1 and 3 of actin by intercalating its aliphatic tail part into the actin molecule as do the other reported F-actin depolymerizing agents. Unexpectedly, this complex structure shows the specific structural features around the trimethylserine moiety, revealed as an important moiety of aplyronine A for cytotoxicity against HeLa cells. Combining this result and our previous one, the moiety should strongly relate to the specific biological activity of aplyronine A; i.e. a potent antitumor effect.
Hirata
Kunio
K
JASRI/SPring-8, 1-1-1 Kouto, Mikazuki-cho, Sayo-gun, Hyogo 679-5198 Japan.
Muraoka
Shin
S
Suenaga
Kiyotake
K
Kuroda
Takeshi
T
Kato
Kenichi
K
Tanaka
Hiroshi
H
Yamamoto
Masaki
M
Takata
Masaki
M
Yamada
Kiyoyuki
K
Kigoshi
Hideo
H
D000199:Actins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001048:Aplysia / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism; D018942:Macrolides; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D012694:Serine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D007783:Lactones; D018942:Macrolides; C104057:aplyronine A; D012694:Serine; D000255:Adenosine Triphosphate