Structure basis for antitumor effect of aplyronine A

Kunio Hirata, Shin Muraoka, Kiyotake Suenaga, Takeshi Kuroda, Kenichi Kato, Hiroshi Tanaka, Masaki Yamamoto, Masaki Takata, Kiyoyuki Yamada, Hideo Kigoshi

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

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 Å 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.

Original languageEnglish
Pages (from-to)945-954
Number of pages10
JournalJournal of Molecular Biology
Volume356
Issue number4
DOIs
Publication statusPublished - 2006 Mar 3

Keywords

  • Antitumor substance
  • Cytotoxicity
  • F-actin depolymerizing agent
  • Marine macrolide
  • X-ray crystallography

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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