Structure basis for antitumor effect of aplyronine A

被引：70

作者：

Hirata, K

Muraoka, S

Suenaga, K

Kuroda, T

Kato, K

Tanaka, H

Yamamoto, M

Takata, M

Yamada, K

Kigoshi, H

机构：

[1] JASRI S Pring 8, Mikazuki, Hyogo 6795198, Japan

[2] JST, CREST, Kawaguchi, Saitama 3320012, Japan

[3] Univ Tsukuba, Dept Chem, Tsukuba, Ibaraki 3058571, Japan

[4] Shimane Univ, Dept Mat Sci, Matsue, Shimane 6908504, Japan

[5] RIKEN SPring 8, Mikazuki, Hyogo 6795148, Japan

[6] Nagoya Univ, Chikusa Ku, Nagoya, Aichi 4648602, Japan

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2006年 / 356卷 / 04期

关键词：

F-actin depolymerizing agent; antitumor substance; X-ray crystallography; marine macrolide; cytotoxicity;

D O I：

10.1016/j.jmb.2005.12.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 angstrom 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. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：945 / 954

页数：10

共 44 条

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