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Document drug from the pocket is confirmed by crystallographic analysis showing that the Phe side chain in the Cys rarrow.gif Phe mutation occupies the site which would be occupied by a drug if it were bound. B. Compensation Mutants Page 515 More intriguing and more difficult to understand are the compensation mutants. These viruses bind compounds within their hydrophobic pockets, but are still able to replicate and are therefore able to compensate for the bound drug (Table 1, Figure 4). These mutations, like the mutations that convey acidresistance phenotypes, cluster about the hydrophobic pocket of VP1 [27,28,92]. Two hypothesis have been presented in order to explain the behavior of the compensation mutants. The first suggests that there is a link between the binding of receptor by virion and its ability to bind compounds in the VP1 pocket. The second hypothesis suggests that the effect of a mutation on protein stability leads to the drug-resistant phenotype. These two hypotheses are not mutually exclusive. Linked-Binding Hypothesis The compensation mutants can be subdivided into those that occur on the canyon floor and those that are inside the VP1 hydrophobic pocket. The linked-binding hypothesis suggests that the subset of compensation mutations that occur on the canyon floor increase the binding affinity of receptor. An increase in binding for one of these mutants, Val1153 rarrow.gif Ile, has been observed [28]. This increased binding would then in turn cause a decrease in the affinity of the capsid for the drug. This would result in the drug being less effective in inhibiting uncoating. The second subset of compensation mutants are those that occur inside the hydrophobic pocket but do not interact with the receptor binding site. These mutations might directly decrease drug-binding affinity in the VP1 pocket due to decreased hydrophobic interactions caused by the smaller amino acid side chains [27]. In both subsets of mutations, the binding affinity of a drug is reduced either directly or through the effects of receptor binding. This decreased affinity for drug would be displayed as a drugresistant phenotype. Stabilization—Destabilization Hypothesis An alternative explanation for the behavior of the drug compensation mutants suggests that these mutants allow for increased conformational flexibility in the capsid. This increased conformational flexibility would compensate for the decrease in flexibility, which is manifested by decreased acid or thermal lability, induced by the binding of drug. The increase in flexibility would allow a http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_515.html [4/9/2004 12:45:42 AM]
Document conformational transition to occur, presumably near the GH loop, that would be required for viral uncoating. The conformational transition would lead to productive uncoating, even in the presence of bound drug. Page 516 This hypothesis suggests that drug-resistant mutations would be of the type that destabilize protein structures. Such mutations are typically from larger to smaller side chains or from highly branched to less branched side chains [43–45]. Four of five observed compensation mutants are of this type (Table 1). The remaining mutant, Val1153 rarrow.gif Ile, while a priori might not be predicted to destabilize the capsid, has been shown experimentally to decrease viral thermostability when compared with native HRV14 [28]. The advantage of the stabilization-destabilization hypothesis is that it allows for a single mechanism of resistance for both compensation mutants occurring in the hydrophobic pocket as well as those that are outside the pocket near the receptor binding site. Both of these sites are close to the GH loop of VP1 that becomes disordered under acidic conditions. This stabilization—destabilization hypothesis also explains the behavior of acid-resistant mutants, which are predominately of the type which should stabilize a protein to conformational changes. Wild-type viruses have a preferred stability profile, which allows uncoating under the proper conditions. Mutations or addition of drug can perturb this profile, resulting in decreased replication. A second perturbation might then compensate for the first, restoring virulence (Figure 11). This behavior has been observed in HRV1A, in which mutants have been isolated that require presence of drug to replicate. These mutations are more acid-labile Figure 11 The effects of various rhinovirus manipulations. The solid line depicts the native rhinovirus uncoating profile. Mutations and drugs can effect this profile to make the virus more or less stable to pH- or temperature-induced changes. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_516.html (1 of 2) [4/9/2004 12:45:46 AM]
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Document dine) and didanosine (dide
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Page 591 and 592: Document Page 478 lished—was asso
Page 593 and 594: Document VI. Conclusion Page 480 It
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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