Hyb

9 Lessons Learned from Ribosome/Drug Complexes

P2'

Figure 6.11. An overall view of macrolide/ketolide binding. Several arms extend from the aglycone ring. Desosamine occupies the PI binding pocket and makes interactions to multiple nucleotides including A2058. Cladinose occupies the P2 binding pocket and stacks with C2610. Extensions from cladinose extend into another pocket, P2'. Ke-tolide antibiotics have either extensions or aiyl extensions from C6, both extensions seem to interact with a pocket involving Therefore, a macrolide analog presumably cannot have both types of extensions.

binding involved (10-14). Earlier NMR structures of aminoglycoside/RNA complexes confirmed the predicted importance of electrostatic interactions between drug amino groups and RNA phosphate groups, but also illustrated other important features of drug binding, such as hydrogen bonds to nucleo-bases and stacking of drug sugars atop base pairs (59, 60). Previous sections described the binding of four classes of drugs in detail; given their level of chemical diversity, it shouldn't surprise anyone that the observed modes of binding were very different. Other antibiotic/ RNA complexes have been solved (8-12), adding further to the collective knowledge of interactions; like the drugs discussed above, each brings knowledge of previously unknown modes of interaction. Their structures plus the structure of linezolid, a recently approved synthetic antibiotic, are drawn in Fig. 6.12.

Streptomycin binds to a site that ties together multiple helices almost exclusively through hydrogen bonds and salt bridges to backbone phosphates, whereas compounds such as hygromycin B bind to a pocket within an expanded major groove through several hydrogen bonds to nucleotide bases but with no phosphate contacts (10). Paromomycin and gentamicin share the same pocket within a major groove and make numerous contacts to both backbone phosphates and nucleotide bases (10, 59, 60).

Some antibiotics, such as erythromycin and chloramphenicol, seem to rely heavily on hydrophobic interactions to provide necessary binding energy, but there is substantial variation in how this is accomplished. For example, aromatic rings from tetracycline and pactamy-cin stack with nucleotide bases, whereas paromomycin, gentamicin, and erythromycin contain sugars that stack atop the aromatic nucleotide bases (10,14,60). Pactamycin illustrates the latter phenomenon in reverse: a ri-bose sugar from 16S rRNA stacks atop one of pactamycin's two aromatic rings (11).

Two drugs, chloramphenicol and tetracycline, interact with rRNA through Mg2"1" atoms that are coordinated by both the drugs and the RNA phosphate oxygens (11, 14). Shared metal coordination is not a common interaction between drug and proteins; it remains to be seen if this is a common phenomenon for RNA/antibiotic complexes or not.

Table 6.1 lists several ribosome binding antibiotics and one novel compound, linezolid oh -O

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