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Document Page 304 location). Another is that both the backbone and the side chains of residues 8– 16 are less well defined than the bulk of the structure due to a lack of medium- and long-range NMR restraints between residues in this loop and the rest of the molecule, as illustrated in Figure 5. These problems are exacerbated in the case of AP-A and AP-B by the presence of multiple conformers in solution, one cause of which is cistrans isomerism about the Gly40-Pro41 peptide bond [52]. The additional peak overlap caused by these conformers limited the number of NOE restraints that could be obtained from the spectra. Finally, the structures available at present are for the free ligand and we have no information on how much these structures might change upon binding to the sodium channel. One way of addressing the issue of a lack of precision in the locations of functionally important side chains is to determine the range of conformational space available to them in different ligands. To this end, we undertook a detailed comparison of the structures of AP-A and AP-B in solution [47]. This proved to be a useful exercise both in terms of defining the positions of side chains known to be important for cardiotonic activity and identifying neighboring residues which might also be involved [47]. Models have been described in the literature for AP-B [53] and Bunodosoma granulifera toxins II (Bg II) [26]. The AP-B model was derived from the structure of Sh I using energy minimization and the Bg II model from that of BDS I using energy minimization and 10 ps of dynamics. In both cases the calculations appear to have been carried out for the molecule in vacuo without the use of a distancedependent dielectric, under which conditions the positions of the charged side chains on the surface are likely to be distorted. Visual comparison of the model of AP-B [53] with the experimentally determined solution structure [47] indicates significant differences in side-chain orientations. IV. Residues Essential For Cardiotonic Activity Information about which residues are essential for the cardiac stimulatory activity of the sea anemone toxins has been obtained from selective chemical modification and proteolysis studies, comparisons among naturally occurring sequences, and, most recently, site-directed mutagenesis. Although there are some discrepancies among the inferences drawn from different studies and different techniques, a consensus is emerging regarding the location of the cardioactive pharmacophore. Ideally, only effects on cardiac tissue should be considered, but doing so would exclude some useful data on activity against mammalian nerve preparations. However, data obtained on the Type 2 toxins or on the activity of Type 1 toxins on nonmammalian tissues will not be discussed in detail. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_304.html [4/5/2004 5:23:24 PM]
Document A. Chemical Modification Page 305 A number of chemical modification studies have been carried out on the sea anemone toxins. As discussed previously [24], the results of these studies have to be interpreted with some caution because of less than rigorous characterization of the reaction products in many cases. Nevertheless, in the Type 1 toxins it appears that one or both of the Asp7 and Asp9 carboxylates are required for activity, as well as one or both of the Lys37 and Lys48 ε-ammonium groups [24,27,54]. The C-terminal carboxylate appears not to be essential, whereas the N-terminal ammonium appears to have some role, although the various studies give a confusing view of its importance. There are also conflicting data on the importance of His34 and His39 but it seems that at least one of them might be important. Both are located in the vicinity of other residues found to be necessary for activity, but His39 is in close contact with Asp7 and Lys37 and on this basis may be expected to be the more important. Although the available evidence points to a role for one or both of the Asp7 and Asp9 carboxylates in cardiotonic activity, it has not been established that either residue makes contact with the sodium channel. As indicated above, the carboxylate of Asp9 participates in a hydrogen bond to the backbone amide of Cys6, so its role may be structural. The carboxylate of Asp7 is close to the side chains of Lys37 and His39 and is exposed to the solvent, making it a more likely candidate for direct interactions with the sodium channel. The only evidence for its importance, however, is indirect, coming from the observation that its replacement by Asn in synthetic Sh I abolished toxicity to crabs [55]. Considerable confusion has surrounded the role of Arg14, which is conserved throughout the Type 1 and Type 2 toxins. A recent study has shown, however, that modification of Arg14 in AP-A with 1,2cyclohexanedione under conditions where the positive charge is maintained did not affect positive inotropic activity [54]. This study also showed indirectly that any contact the Arg14 side chain makes with the sodium channel must be relatively loose: although the adduct is active, it is no longer susceptible to tryptic proteolysis, indicating that the modified side chain cannot be accommodated in the substrate binding site of the protease. The conclusion that the positive charge on Arg14, but not its exact spatial location, might be important for activity is consistent with the results of site-directed mutagenesis experiments discussed below. B. Selective Proteolysis When AP-A was treated with trypsin only the Arg14 to Gly15 peptide bond was cleaved [56]. The resulting derivative lacked cardiotonic activity but its binding affinity for the rat brain sodium channel was reduced by less than an order of magnitude (Llewellyn LE et al., unpublished results). Its overall structure, as http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_305.html [4/5/2004 5:23:26 PM]
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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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