The cystine knot structure of ion channel toxins and related polypeptides

被引:278
作者
Norton, RS [1 ]
Pallaghy, PK [1 ]
机构
[1] Biomol Res Inst, Parkville, Vic 3052, Australia
关键词
D O I
10.1016/S0041-0101(98)00149-4
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
An increasing number of ion channel toxins and related polypeptides have been found to adopt a common structural motif designated the inhibitor cystine knot motif (Pallaghy P. K., Nielsen, K. J., Craik, D. J., Norton, R. S. (1994) A common structural motif incorporating a cystine knot and triple-stranded beta-sheet in toxic and inhibitory polypeptides. Protein Science 3, 1833-1839). These globular, disulfide-stabilized molecules come from phylogenetically diverse sources, including spiders, cone shells, plants and fungi, and have various functions, although many target voltage-gated ion-channels. The common motif consists of a cystine knot and a triple-stranded, anti-parallel beta-sheet. Examples of ion-channel toxins known to adopt this structure are the omega-conotoxins and omega-agatoxins, and, more recently, robustoxin, versu-toxin and protein 5 from spiders, as well as kappa-conotoxin PVIIA and conotoxin GS from cone shells. The variations on the motif structure exemplified by these structures are described here. We also consider the sequences of several polypeptides that might adopt this fold, including SNX-325 from a spider, delta-conotoxin PVIA and the mu O-conotoxins from cone shells, and various plant and fungal polypeptides. The interesting case of the two- and three-disulfide bridged binding domains of the cellobiohydrolases from the fungus Trichoderma reesei is also discussed. The compact and robust nature of this motif makes it an excellent scaffold for the design and engineering of novel polypeptides with enhanced activity against existing targets, or with activity against novel targets. (C) 1998 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1573 / 1583
页数:11
相关论文
共 58 条
[1]  
ADAMS ME, 1993, MOL PHARMACOL, V44, P681
[2]  
ARAI K, 1995, J BIOMOL NMR, V5, P297
[4]   PROTEIN DATA BANK - COMPUTER-BASED ARCHIVAL FILE FOR MACROMOLECULAR STRUCTURES [J].
BERNSTEIN, FC ;
KOETZLE, TF ;
WILLIAMS, GJB ;
MEYER, EF ;
BRICE, MD ;
RODGERS, JR ;
KENNARD, O ;
SHIMANOUCHI, T ;
TASUMI, M .
JOURNAL OF MOLECULAR BIOLOGY, 1977, 112 (03) :535-542
[5]   Population statistics of protein structures: Lessons from structural classifications [J].
Brenner, SE ;
Chothia, C ;
Hubbard, TJP .
CURRENT OPINION IN STRUCTURAL BIOLOGY, 1997, 7 (03) :369-376
[6]   ANTIMICROBIAL PEPTIDES FROM AMARANTHUS-CAUDATUS SEEDS WITH SEQUENCE HOMOLOGY TO THE CYSTEINE GLYCINE-RICH DOMAIN OF CHITIN-BINDING PROTEINS [J].
BROEKAERT, WF ;
MARIEN, W ;
TERRAS, FRG ;
DEBOLLE, MFC ;
PROOST, P ;
VANDAMME, J ;
DILLEN, L ;
CLAEYS, M ;
REES, SB ;
VANDERLEYDEN, J ;
CAMMUE, BPA .
BIOCHEMISTRY, 1992, 31 (17) :4308-4314
[7]  
CAMMUE BPA, 1992, J BIOL CHEM, V267, P2228
[8]  
CHAGOLLALOPEZ A, 1994, J BIOL CHEM, V269, P23675
[9]   SOLUTION CONFORMATION OF A SYNTHETIC BIS-HEADED INHIBITOR OF TRYPSIN AND CARBOXYPEPTIDASE-A - NEW STRUCTURAL ALIGNMENT BETWEEN THE SQUASH INHIBITORS AND THE POTATO CARBOXYPEPTIDASE INHIBITOR [J].
CHICHE, L ;
HEITZ, A ;
PADILLA, A ;
LENGUYEN, D ;
CASTRO, B .
PROTEIN ENGINEERING, 1993, 6 (07) :675-682
[10]   REFINED 3-DIMENSIONAL SOLUTION STRUCTURE OF INSECT DEFENSIN-A [J].
CORNET, B ;
BONMATIN, JM ;
HETRU, C ;
HOFFMANN, JA ;
PTAK, M ;
VOVELLE, F .
STRUCTURE, 1995, 3 (05) :435-448