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Revisiting the Structures of Several Antibiotics Bound to the Bacterial Ribosome

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Revisiting the Structures of Several Antibiotics Bound to the Bacterial Ribosome Revisiting the structures of several antibiotics bound to the bacterial ribosome David Bulkleya,1, C. Axel Innisb,1, Gregor Blahab, and Thomas A. Steitza,b,c,2 aDepartments of Chemistry and bMolecular Biophysics and Biochemistry, Yale University, cHoward Hughes Medical Institute, New Haven, CT 06511 Edited* by V. Ramakrishnan, Medical Research Council, Cambridge, United Kingdom, and approved August 17, 2010 (received for review June 18, 2010) The increasing prevalence of antibiotic-resistant pathogens rein- decided to revisit the structure of chloramphenicol bound to the forces the need for structures of antibiotic-ribosome complexes ribosome for several reasons: (i) only one such structure is avail- that are accurate enough to enable the rational design of novel able, and it originated from the same study that yielded the struc- ribosome-targeting therapeutics. Structures of many antibiotics ture of a bacterial ribosome in complex with erythromycin that in complex with both archaeal and eubacterial ribosomes have was inconsistent with later structural work at higher resolution; ii been determined, yet discrepancies between several of these ( ) in contrast with the distinctive lactone ring of macrolides, models have raised the question of whether these differences arise chloramphenicol lacks obvious structural features that would facilitate its placement into a medium resolution electron density from species-specific variations or from experimental problems. iii Our structure of chloramphenicol in complex with the 70S ribo- map; ( ) a number of minor inconsistencies between the sole available structural model and biochemical data warrant addi- some from Thermus thermophilus suggests a model for chloram- tional validation of the former (14–17). The structures of the phenicol bound to the large subunit of the bacterial ribosome erythromycin, azithromycin, telithromycin, and chloramphenicol that is radically different from the prevailing model. Further, our complexes with the T. thermophilus 70S ribosome reported here structures of the macrolide antibiotics erythromycin and azithro- are all inconsistent with the earlier published structural studies mycin in complex with a bacterial ribosome are indistinguishable with the D. radiodurans large subunit, but the macrolide com- from those determined of complexes with the 50S subunit of plexes are in complete agreement with the structural conclusions Haloarcula marismortui, but differ significantly from the models from the published H. marismortui large subunit complexes. that have been published for 50S subunit complexes of the eubac- terium Deinococcus radiodurans. Our structure of the antibiotic Results telithromycin bound to the T. thermophilus ribosome reveals a Datasets for the chloramphenicol, erythromycin, and azithromy- lactone ring with a conformation similar to that observed in the cin ribosome complexes were collected from single crystals, H. marismortui and D. radiodurans complexes. However, the whereas the data from the complex with telithromycin was alkyl-aryl moiety is oriented differently in all three organisms, and obtained from three separate crystals. All crystals belonged to the T. thermophilus primitive orthorhombic space group P212121 and diffracted to the contacts observed with the ribosome are con- – sistent with biochemical studies performed on the Escherichia coli 3.1 3.3 Å. Statistics for the data can be seen in Table S1. ribosome. Thus, our results support a mode of macrolide binding Chloramphenicol. that is largely conserved across species, suggesting that the quality Chloramphenicol binds directly to the A-site and interpretation of electron density, rather than species specifi- crevice on the 50S ribosomal subunit, occupying the same loca- city, may be responsible for many of the discrepancies between the tion as the aminoacyl moiety of an A-site tRNA (Fig. 1) (18, 19). models. The placement of this drug in the immediate vicinity of the in- coming A-site tRNA is consistent with biochemical experiments (20, 21). The location and orientation of chloramphenicol that we crystal structure ∣ structure-based drug design observe in our complex is completely different from the model that has been published for the D. radiodurans 50S subunit com- ntibiotics that target the translational machinery of bacterial plex (11) (Fig. 1 A–C). Superimposition of the ribosomal RNA Acells are potent inhibitors of prokaryotic pathogens (1), but from the two structures shows that the two chloramphenicol increasing rates of antibiotic resistance among bacteria often models are related by a rotation of approximately 180° and that dampen the effectiveness of common, clinically used antibiotics – the planes of the benzyl rings are orthogonal to one another. (2 5). Recent work has shown that structure-based drug design Additionally, the ion(s) anchoring the molecule to the ribosome exhibits the potential to overcome this problem by chemically differ in their location, number, and identity; the D. radiodurans linking together pairs of known classes of ribosomal inhibitors model posits two putative and as yet unproven magnesium ions to generate novel antibiotics (6–8). The wealth of ribosomal anti- biotics and corresponding resistance mutations suggests that many additional chemical derivatives of existing antibiotics might Author contributions: D.B., C.A.I., G.B., and T.A.S. designed research; D.B., C.A.I., and G.B. be created and could be useful in dealing with resistance, but con- performed research; D.B., C.A.I., and G.B. analyzed data; and D.B., C.A.I., and T.A.S. wrote flicting crystallographically determined models for how some of the paper. Conflict of interest statement: Thomas A. Steitz is a scientific advisor for Rib-X these antibiotics are bound and oriented could be an impediment Pharmaceuticals, a product-driven small molecule drug discovery and development to the design of new hybrid molecules. For example, structures company focused on the structure-based design of unique classes of antibiotics. of several macrolide and ketolide antibiotics in complex with *This Direct Submission article had a prearranged editor. Deinococcus radiodurans the large ribosomal subunits of and Freely available online through the PNAS open access option. Haloarcula marismortui (9–12) have shown significant differences Data deposition: The atomic coordinates for the various ribosome-antibiotic complexes in the orientations and conformations of the drugs, in particular have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 3OGE/3OGY/ with respect to the lactone rings and the contacts they make with 3OH5/3OH7 (chloramphenicol), 3OHC/3OHD/3OHJ/3OHK (erythromycin), 3OHY/3OHZ/ the ribosome. Because it has been suggested that the discrepan- 3OI0/3OI1 (azithromycin), and 3OI2/3OI3/3OI4/3OI5 (telithromycin)]. cies between these models result from species-specific differences See Commentary on page 17065. in the ribosomal RNA (13), we chose to address these issues by 1D.B. and C.A.I. contributed equally to this work. determining the structures of the 70S ribosome from the eubac- 2To whom correspondence should be addressed. E-mail: [email protected]. Thermus thermophilus terium in complex with the antibiotics This article contains supporting information online at www.pnas.org/lookup/suppl/ erythromycin, azithromycin, and telithromycin. In addition, we doi:10.1073/pnas.1008685107/-/DCSupplemental. 17158–17163 ∣ PNAS ∣ October 5, 2010 ∣ vol. 107 ∣ no. 40 www.pnas.org/cgi/doi/10.1073/pnas.1008685107 Downloaded by guest on September 24, 2021 SEE COMMENTARY Fig. 1. Interaction between chloramphenicol and the ribosome. (A) An unbiased 3.2-Å-resolution Fo-Fc difference electron density map contoured at þ3σ calculated using amplitudes from T.th. 70S ribosome crystals soaked with 500 μM chloramphenicol. The chloramphenicol moiety is shown in orange, along with a potassium ion mediating the interaction between the drug and the ribosome. (B) The same electron density as shown in A, with the chloramphenicol moiety and two magnesium ions modeled in the D.ra. 50S structure (11) shown in red. The T.th. 70S ribosome and the D.ra. 50S subunit structures were superimposed using equivalent phosphate atoms in the 23S rRNA and the program Lsqman (54). The superimposed structures had an rmsd of 1.21 Å for 2,800 atoms. (C) Overlay of the chloramphenicol molecules modeled in the T.th. 70S (orange) and D.ra. 50S (red) complex structures. Both the model coordinates and the view are the same as in A and B.(D) Overlay of the chloramphenicol molecule modeled in the T.th. 70S complex (orange) and the anisomycin molecule modeled in H.ma. 50S complex (blue). The superimposed structures had an rmsd of 1.53 Å for 2,800 atoms. (E) Interactions between chloramphenicol and the T.th. 70S ribosome. The drug is shown as green sticks, and key interacting residues in the ribosome are shown in white. The potassium ion is displayed as a gray BIOPHYSICS AND sphere. (F) A surface representation of the binding pocket for chloramphenicol in the T.th. 70S ribosome, showing surface complementarity between the drug COMPUTATIONAL BIOLOGY (orange) and the A-site crevice in the ribosome as well as the aminoacyl group (blue) of bound phe-tRNA (37). holding the drug in place, whereas our data implicate a single col is bound, which is consistent with the structure we observe potassium ion whose location in the peptidyl transferase center (29, 30) (Fig. S1D). (PTC) is consistent with previous biochemical and crystallo- The acetylation
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