Turning a scorpion toxin into an antitumor miniprotein.
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.
Li
Chong
C
Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, Maryland 21201, USA.
Liu
Min
M
Monbo
Juahdi
J
Zou
Guozhang
G
Li
Changqing
C
Yuan
Weirong
W
Zella
Davide
D
Lu
Wei-Yue
WY
Lu
Wuyuan
W
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D012604:Scorpion Venoms / Q000737:chemistry*; D012605:Scorpions / Q000737:chemistry*; D040681:Structural Homology, Protein
D000970:Antineoplastic Agents; D012604:Scorpion Venoms
J Am Chem Soc. 2008 Mar 12;130(10):2948-9
18271592
J Struct Biol. 2004 Mar;145(3):289-94
14960379
Science. 1996 Nov 8;274(5289):948-53
8875929
Science. 2004 Feb 6;303(5659):844-8
14704432
J Biol Chem. 2004 Aug 13;279(33):34562-9
15178692
J Am Chem Soc. 2007 Nov 28;129(47):14578-9
17983240
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3933-8
18316739
Biochemistry. 2004 Apr 6;43(13):3764-71
15049683
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13091-6
10557278
Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83
17380161
Cancer Res. 2007 Sep 15;67(18):8810-7
17875722
Chembiochem. 2006 Jan;7(1):29-31
16397877
Adv Drug Deliv Rev. 2005 Feb 28;57(4):597-608
15722166
Adv Drug Deliv Rev. 2005 Feb 28;57(4):559-77
15722164
Nat Biotechnol. 2003 Jan;21(1):71-6
12483221
J Cell Sci. 2007 Feb 1;120(Pt 3):371-8
17251377
Biopolymers. 2007;88(5):657-86
17427181
Adv Drug Deliv Rev. 2005 Feb 28;57(4):579-96
15722165
Curr Biol. 1997 Nov 1;7(11):860-9
9382809
Nat Rev Cancer. 2006 Dec;6(12):909-23
17128209