将一种蝎子毒素转化为一种抗肿瘤微型蛋白。
Turning a scorpion toxin into an antitumor miniprotein.
作者信息
Li Chong, Liu Min, Monbo Juahdi, Zou Guozhang, Li Changqing, Yuan Weirong, Zella Davide, Lu Wei-Yue, Lu Wuyuan
机构信息
Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, Maryland 21201, USA.
出版信息
J Am Chem Soc. 2008 Oct 15;130(41):13546-8. doi: 10.1021/ja8042036. Epub 2008 Sep 18.
Abstract
The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53 and are important molecular targets for anticancer therapy. Grafting four residues of p53 critical for MDM2/MDMX binding to the N-terminal alpha-helix of BmBKTx1, a scorpion toxin isolated from the venom of the Asian scorpion Buthus martensi Karsch, converts the miniature protein into an effective inhibitor of p53 interactions with MDM2 and MDMX. Additional mutations enable the 27-residue miniprotein inhibitor to traverse the cell membrane and selectively kill tumor cells in a p53 dependent manner.
摘要
癌蛋白MDM2和MDMX对肿瘤抑制蛋白p53的活性和稳定性起负调控作用，是抗癌治疗的重要分子靶点。从亚洲蝎马氏钳蝎毒液中分离出的一种蝎毒素BmBKTx1，将对MDM2/MDMX结合至关重要的四个p53残基嫁接到其N端α螺旋上，可将这种微型蛋白转化为p53与MDM2和MDMX相互作用的有效抑制剂。进一步的突变使这种由27个残基组成的微型蛋白抑制剂能够穿过细胞膜，并以p53依赖的方式选择性杀死肿瘤细胞。
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