6of1

Crystal structure of the Thermus thermophilus 70S ribosome in complex with dirithromycin and bound to mRNA and A-, P-, and E-site tRNAs at 2.80A resolution

spinqualitylabelsall models 6of1, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6of1 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 2.8Å Ligands: 0TD, 2MA, 2MG, 2MU, 4OC, 4SU, 5MC, 5MU, 6MZ, 7MG, CM0, DI0, K, M2G, MA6, MG, OMG, PSU, UR3, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function RL25_THET8 This is one of 3 proteins that mediate the attachment of the 5S rRNA onto the large ribosomal subunit.[HAMAP-Rule:MF_01334] Publication Abstract from PubMed Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate drug binding to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for the new chemical moieties improving the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a "classic" macrolide dirithromycin, which has extended (2-methoxyethoxy)-methyl side chain attached to the C9/C11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion, its side chain forms lone pair-pi stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens. Structure of dirithromycin bound to the bacterial ribosome suggests new ways for rational improvement of macrolides.,Khabibullina NF, Tereshchenkov AG, Komarova ES, Syroegin EA, Shiriaev DI, Paleskava A, Kartsev VG, Bogdanov AA, Konevega AL, Dontsova OA, Sergiev PV, Osterman IA, Polikanov YS Antimicrob Agents Chemother. 2019 Apr 1. pii: AAC.02266-18. doi:, 10.1128/AAC.02266-18. PMID:30936109 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ribosomal protein THX 3D structures Ribosome 3D structures

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