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Document Page 306 monitored by NMR, was unchanged, although it should be noted that the structure of the loop containing Arg14 was not well defined in either native or trypsinised AP-A. That the backbone structure was largely unaffected was confirmed by the observation that the NH and CαH chemical shifts were unaltered except in the immediate vicinity of the cleavage (which is the site of a reverse turn in AP-A [46]) and the N-terminal regions of the loop and the second strand of the sheet. It is possible that perturbations of functionally important groups near the start of the loop may be responsible for the lack of activity of the trypsinised derivative, and now that a high-resolution structure is available for AP-A a more detailed comparison with the cleavage product would be useful. Other possible explanations for the lack of activity are that the position of the Arg14 side chain relative to other key residues in the molecule is more important than suggested by chemical modification and site-directed mutagenesis data, or that the introduction of additional charges associated with the new termini affects activity. Endoproteinase LysC cleaved AP-A between Lys37 and Ala38 to yield a derivative with cardiotonic activity an order of magnitude lower than that of the parent molecule (Monks SA and Norton RS, unpublished results). This reduction in activity could be a consequence of local conformational perturbations. Treatment of AP-B with carboxypeptidase B removed Lys49, resulting in only a two-fold reduction in cardiotonic activity (Monks SA and Norton RS, unpublished results). C. Sequence Comparisons Among the Type 1 toxins shown in Figure 2, the Bc and Bg toxins (from the genus Bunodosuma) form a subgroup with characteristic differences from the Anemonia and Anthopleura toxins at residues 5, 12–13 and 37–42. In addition, the Bg toxins also have Asp7 rarrow.gif Lys and Gly27 rarrow.gif Arg substitutions. A potent toxin in mice [26], the cardiac stimulatory activity of Bg II has not been reported. The potent activity of Bg II was ascribed to its abundance of positive charges [26]. Ignoring the histidines, which at least in AP-A and ATX II would be predominantly in their neutral forms at physiological pH [57], Bg II has six positively charged side chains and only one negatively charged side chain, whereas, AP-A has three and two respectively, and AP-B has five and two. As discussed below, however, it may be that an abundance of positive charge is associated with a lack of discrimination between the neuronal and cardiac sodium channels, as found for the scorpion α-toxins. Comparison of the activities of Af I and Af II is useful because of their close similarity. Differences between Af I and Af II are Ala3 rarrow.gif Pro, Asn12 rarrow.gif Ser, Thr21 rarrow.gif Ile, and an additional Gly at the N-terminus. Inspection of the sequences in Figures 2 shows that the identity of residue 3 correlates with that of residue 21, Ala or Ser at 3 co-occurring with Thr21, and Pro 3 with Ile21 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_306.html [4/5/2004 5:23:44 PM]
Document Page 307 (the exception is ATX Ib [19,24], which has Pro 3 and Thr21, but it is not known if this has the same local structure). Residues 3 and 21 are juxtaposed in the β sheet [46–48] and the effect of switching Ser3/Thr21 to Pro3/Ile21 can be assessed by comparing the structures of AP-A [46] and AP-B [47]. It appears that this leads to a distortion of the sheet between the second and third residues but causes no significant perturbations to the overall structure. In the calculated structures of AP-A a Va12 NH rarrow.gif Leu22 CO hydrogen bond was found but this was not present in the AP-B structures, presumably as a result of the local differences. Comparing Af I and Af II, the combination of the Ala3/Thr21 to Pro3/Ile21 switch plus the addition of an extra Gly at the N-terminus of Af II would be expected to alter the local conformation at the N-terminus. The fact that the cardiac stimulatory activities of the two are the same [58] therefore implies that the N-terminus is not important functionally. This inference is conditional on the effect on activity of the only other difference between Af I and Af II, Asn12 rarrow.gif Ser, being minimal. In the Type 1 toxins, Ser is found more often than Asn at position 12, while in the Type 2 toxins, replacement of Asn12 by Tyr increases toxicity in mice by a factor of two [24,27]. Thus, it is possible that the presence of Ser in Af II slightly favors cardiac activity while the changes at the N-terminus might reduce it slightly; the main conclusion to be drawn, however, is that neither change has a significant effect. The lack of effect of changes at the N-terminus is consistent with the results from expression of AP-B [59], where a Gly-Arg extension at the N-terminus had no effect on activity. At seven locations AP-B differs from AP-A. Two of these, Ser3 rarrow.gif Pro and Thr21 rarrow.gif Ile, were discussed above. Two more, Leu24 rarrow.gif Phe and Thr42 rarrow.gif Asn, are conservative changes located in or at the start of loops that are not in the immediate vicinity of the sodium channel binding surface and would not be expected to have a direct effect on activity. This leaves Ser12 rarrow.gif Arg, Val13 rarrow.gif Pro, and Gln49 rarrow.gif Lys, which do have functional significance, as discussed in the following section. It is important to note that there are several residues that are common to all of the long toxins and serve to maintain the biologically active conformations of these molecules. The clearest examples of residues in this category are the six half-cystines, although we believe that the Gly10-Pro11 sequence may influence the structure and flexibility of the Arg14-containing loop [46] (at the other end of this loop Thr17 and/or Ser19-Gly20 may also be important). Also conserved, Trp33 is probably important structurally even though its surroundings are different in the Type 1 and Type 2 toxins. It is also interesting that in ATX Ia, which is a potent crustacean neurotoxin but a poor mammalian cardiac stimulant, Lys37 and both histidines are missing, suggesting that one or more of these side chains may be important in promoting specificity for the mammalian cardiac sodium channel. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_307.html [4/5/2004 5:23:45 PM]
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Structure-based Drug Design 14 Stru
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Document B. Pharmacology Figure 1 T
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Document replacements, 563-565 1-am
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Document inhibitor binding, 323, 33
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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
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Document [Protease targets] serinyl
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