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Document D. Site-Directed Mutagenesis Page 308 The complete synthesis of AP-A has been reported [60] but so far this approach has not been pursued to generate analogues. More productive has been the analysis of analogues produced by site-directed mutagenesis, following the successful cloning and expression of AP-B [59]. A series of single-site mutations [61,62] showed that R14A, K48A, and K49A had affinities for the cardiac sodium channel that were, respectively, only 3.2-, 2.9-, and 2.4-fold lower than that of native AP-B, while R12A had an 8.5-fold lower affinity. These results suggested that amongst the cationic side chains only Arg12 was significant for activity. Recent data on double mutations [53] indicates that the situation is not quite that simple. For example, the R12S-R14Q double mutant had a 72-fold lower affinity for the neuronal sodium channel whereas the R12S and R14Q mutants individually had 5.9- and 2.4-fold lower affinities, respectively, which should combine to produce only a 14-fold effect. It appears that the presence of one cationic side chain in the Arg14 loop may be sufficient for activity and that its exact location can vary somewhat. It would be interesting to know if the same applies to the C-terminus, where Lys48 and Lys49 may be able to compensate for one another. However, the proposal that the cationic side chains of residues 12, 14, and 49 form a cluster [53] is not consistent with the solution structure of AP-B [47]. A similar situation appears to exist in the ω-conotoxins, which possess 5–7 net positive charges. Substitution of individual cationic groups had a relatively minor effect on affinity for the voltage-gated calcium channel, whereas replacement of several had a significant effect, greater than that expected from the sum of the individual effects [63,64]. A further outcome of analyses of the double mutants was that the cationic side chains at positions 12 and 49 in AP-B seem to favor binding to the neuronal over the cardiac sodium channel. Thus, the R12S- R49Q double mutant, in which residues 12 and 49 in AP-A, had a 37-fold lower affinity for the neuronal channel but only a 5-fold lower affinity for the cardiac channel relative to native AP-B [53]. In fact, the affinity of this double mutant for the cardiac channel was lower than that of AP-A, implying that one or more of the other five differences between AP-A and AP-B might decrease affinity for the cardiac channel. It seems, therefore, that while AP-A is slightly less potent than AP-B on cardiac channels, it has greater selectivity for the cardiac channel when measured in sodium flux experiments. In voltageclamp experiments AP-A and AP-B favor the cardiac channel to similar degrees [53]. V. Other Ligands for Site 3 on the Sodium Channel A. Sea Anemone Toxins Apart from the “long” sea anemone polypeptides that are the main focus of our interest, there are two other classes of anemone polypeptides that bind at or near http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_308.html [4/5/2004 5:23:47 PM]
Document Page 309 site 3 on the sodium channel. The first of these are the short anemone polypeptides [19,24] such as ATX III [38] and PaTX [39], which are neurotoxic to crustacea. The polypeptide ATX III, which consists of 27 residues cross-linked by three disulfide bonds, and PaTX, which has 31 residues and four disulfides, can be aligned such that 16 residues are identical. The three disulfides in ATX III are linked in a 1–5/2–4/3–6 pattern in the same way as in the long polypeptides [65], but the only other similarity at the level of primary structure is a GCPXG sequence corresponding to residues 28–32 of AP-A. Although neurotoxic to crustacea, ATX III is inactive as a positive inotrope [28], suggesting that it possesses an appropriate structural scaffold to interact with site 3 but lacks key side chains required for interaction with the cardiac channel. Nevertheless, the smaller size of ATX III makes it an attractive candidate for further study, with the aim of engineering into it the ability to bind to the cardiac channel. The welldefined solution structure for this toxin [65] provides and essential basis for such an effort. The Anemonia sulcata polypeptides BDS I and II [40], which were claimed to have antihypertensive and antiviral activity, also bind to site 3 on neuronal sodium channels and have weak negative inotropic activity [41]. The points of similarity and difference between the solution structures of BDS I [40] and the long anemone polypeptides have been discussed previously [40,41] and will not be reiterated here; suffice to say that the overall folds are similar but the Arg14 loop in the long polypeptides is truncated in BDS I and the molecule lacks several residues that have been shown to be important for activity. B. Scorpion Toxins The scorpion α-toxins have been shown to bind to site 3 on the voltage-gated sodium channel [24,27,42]. These polypeptides contain up to 70 residues crosslinked by four disulfide bonds, but show no sequence similarity to the anemone polypeptides. Possible structural similarities have been discussed [24], and in a theoretical model of the anemone toxin Bg II, some of the cationic residues were in similar locations to those in the crystal structure of the scorpion toxin Aah II [26]. It is clear that positively charged residues play an important role in the interactions of sea anemone toxins and scorpion toxins with site 3 on the sodium channel (as indeed they do with other polypeptide toxins binding to other ion channels) but this role may be relatively more important for the TTXsensitive sodium channel in nerve and muscle than for the TTX-insensitive channel of the heart. For example, Bg II, which is more positively charged than AP-A and AP-B (see above), has a higher affinity for neuronal sodium channels [26], and replacement of Arg12 and Lys49 in AP-B with uncharged residues favors its binding to the cardiac channel [53]. Similarly, the scorpion α-toxins bind more tightly to the neuronal channel than the anemone toxins but, as with the Type 2 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_309.html [4/5/2004 5:23:49 PM]
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Document site, 52, 55, 61 triad, 24
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Document factors, 247 Combination t
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document [Human immunodeficiency vi
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Document overview, 103-104, 108-109
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Document [Inhibitors] 2-((3,4-dihyd
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Document antagonistic activity, 416
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
Page 831:
Document [Protease targets] serinyl
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