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

62 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
Externally publishedYes

Fingerprint

Actins
Hares
Aplysia
Synchrotrons
Macrolides
aplyronine A
HeLa Cells
Oceans and Seas
Polymerization
Tail
X-Rays
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Virology

Cite this

Hirata, K., Muraoka, S., Suenaga, K., Kuroda, T., Kato, K., Tanaka, H., ... Kigoshi, H. (2006). Structure basis for antitumor effect of aplyronine A. Journal of Molecular Biology, 356(4), 945-954. https://doi.org/10.1016/j.jmb.2005.12.031

Structure basis for antitumor effect of aplyronine A. / Hirata, Kunio; Muraoka, Shin; Suenaga, Kiyotake; Kuroda, Takeshi; Kato, Kenichi; Tanaka, Hiroshi; Yamamoto, Masaki; Takata, Masaki; Yamada, Kiyoyuki; Kigoshi, Hideo.

In: Journal of Molecular Biology, Vol. 356, No. 4, 03.03.2006, p. 945-954.

Research output: Contribution to journalArticle

Hirata, K, Muraoka, S, Suenaga, K, Kuroda, T, Kato, K, Tanaka, H, Yamamoto, M, Takata, M, Yamada, K & Kigoshi, H 2006, 'Structure basis for antitumor effect of aplyronine A', Journal of Molecular Biology, vol. 356, no. 4, pp. 945-954. https://doi.org/10.1016/j.jmb.2005.12.031
Hirata, Kunio ; Muraoka, Shin ; Suenaga, Kiyotake ; Kuroda, Takeshi ; Kato, Kenichi ; Tanaka, Hiroshi ; Yamamoto, Masaki ; Takata, Masaki ; Yamada, Kiyoyuki ; Kigoshi, Hideo. / Structure basis for antitumor effect of aplyronine A. In: Journal of Molecular Biology. 2006 ; Vol. 356, No. 4. pp. 945-954.
@article{129a5f9448bd47f5a2049e62c833b978,
title = "Structure basis for antitumor effect of aplyronine A",
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 {\AA} 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.",
keywords = "Antitumor substance, Cytotoxicity, F-actin depolymerizing agent, Marine macrolide, X-ray crystallography",
author = "Kunio Hirata and Shin Muraoka and Kiyotake Suenaga and Takeshi Kuroda and Kenichi Kato and Hiroshi Tanaka and Masaki Yamamoto and Masaki Takata and Kiyoyuki Yamada and Hideo Kigoshi",
year = "2006",
month = "3",
day = "3",
doi = "10.1016/j.jmb.2005.12.031",
language = "English",
volume = "356",
pages = "945--954",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Structure basis for antitumor effect of aplyronine A

AU - Hirata, Kunio

AU - Muraoka, Shin

AU - Suenaga, Kiyotake

AU - Kuroda, Takeshi

AU - Kato, Kenichi

AU - Tanaka, Hiroshi

AU - Yamamoto, Masaki

AU - Takata, Masaki

AU - Yamada, Kiyoyuki

AU - Kigoshi, Hideo

PY - 2006/3/3

Y1 - 2006/3/3

N2 - 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.

AB - 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.

KW - Antitumor substance

KW - Cytotoxicity

KW - F-actin depolymerizing agent

KW - Marine macrolide

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=31444433185&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=31444433185&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2005.12.031

DO - 10.1016/j.jmb.2005.12.031

M3 - Article

VL - 356

SP - 945

EP - 954

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 4

ER -