7rq9 | pdb_00007rq9

Crystal structure of the A2058-dimethylated Thermus thermophilus 70S ribosome in complex with iboxamycin, mRNA, deacylated A- and E-site tRNAs, and aminoacylated P-site tRNA at 2.60A resolution

spinqualitylabelsall models 7rq9, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7rq9 is a 20 chain structure with sequence from Thermus thermophilus HB8. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: 0TD, 2MA, 2MG, 31H, 4OC, 4SU, 5MC, 5MU, 6IF, 7MG, F3N, K, M2G, MA6, MG, MIA, OMG, OMU, PSU, UR3, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern(1). For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings(2). Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the [Formula: see text] nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance. A synthetic antibiotic class overcoming bacterial multidrug resistance.,Mitcheltree MJ, Pisipati A, Syroegin EA, Silvestre KJ, Klepacki D, Mason JD, Terwilliger DW, Testolin G, Pote AR, Wu KJY, Ladley RP, Chatman K, Mankin AS, Polikanov YS, Myers AG Nature. 2021 Nov;599(7885):507-512. doi: 10.1038/s41586-021-04045-6. Epub 2021 , Oct 27. PMID:34707295 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ribosome 3D structures

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