1xbp | pdb_00001xbp
Inhibition of peptide bond formation by pleuromutilins: The structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with Tiamulin
Structural highlights
Function[RL14_DEIRA] Forms part of two intersubunit bridges in the 70S ribosome (By similarity). Binds to 23S rRNA.[HAMAP-Rule:MF_01367] [RL24_DEIRA] One of two assembly initiator proteins, it binds directly to the 5'-end of the 23S rRNA, where it nucleates assembly of the 50S subunit (By similarity).[HAMAP-Rule:MF_01326_B] One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit. Contacts trigger factor (TF) when it is bound to the ribosome; this contact may expose a hydrophobic crevice in TF (PubMed:16271892).[HAMAP-Rule:MF_01326_B] [RL6_DEIRA] It is located near the subunit interface in the base of the L7/L12 stalk, and near the tRNA binding site of the peptidyltransferase center (By similarity). This protein binds to the 23S rRNA, and is important in its secondary structure.[HAMAP-Rule:MF_01365] [RL31_DEIRA] Binds the 23S rRNA and interacts with the tRNA in the E site.[HAMAP-Rule:MF_00501] [RL20_DEIRA] Binds directly to 23S rRNA, probably serving to organize its structure.[HAMAP-Rule:MF_00382] [RL25_DEIRA] This is one of 3 proteins that mediate the attachment of the 5S rRNA onto the large ribosomal subunit. This protein has three domains. The N-terminal one is bound on the solvent face, the middle domain fills the space between the 5S rRNA and the L11 arm contacting the 23S rRNA while the C-terminal domain is on the edge of the intersubunit interface and contacts the A site. The protein conformation changes upon binding of a tRNA mimic to the A site, although the mimic does not interact directly with CTC itself, consistent with CTCs presumed role in moderating A site binding.[HAMAP-Rule:MF_01334] [RL21_DEIRA] Binds directly to 23S rRNA, probably serving to organize its structure.[HAMAP-Rule:MF_01363] [RL35_DEIRA] Binds the 23S rRNA.[HAMAP-Rule:MF_00514] [RL27_DEIRA] Binds the 5S and 23S rRNAs and also the tRNA in the P site.[HAMAP-Rule:MF_00539] [RL16_DEIRA] Binds the 5S and 23S rRNAs and is also seen to make contacts with the A and P site tRNAs. Interacts with A site tRNA mimics, and is probably one of the key factors, along with a helix of the 23S rRNA, in positioning tRNA stems in the peptidyl-transferase center.[HAMAP-Rule:MF_01342] [RL19_DEIRA] This protein is located at the 30S-50S ribosomal subunit interface and may play a role in the structure and function of the aminoacyl-tRNA binding site (By similarity). Binds the 23S rRNA.[HAMAP-Rule:MF_00402] [RL34_DEIRA] Binds the 23S rRNA.[HAMAP-Rule:MF_00391] [RL5_DEIRA] This is 1 of the proteins that binds and probably mediates the attachment of the 5S RNA into the large ribosomal subunit, where it forms part of the central protuberance. In the 70S ribosome it contacts protein S13 of the 30S subunit (bridge B1b), connecting the 2 subunits; this bridge is implicated in subunit movement (By similarity). Contacts the P site tRNA; the 5S rRNA and some of its associated proteins might help stabilize positioning of ribosome-bound tRNAs.[HAMAP-Rule:MF_01333_B] [RL32_DEIRA] Forms a cluster with L17 and L22, and with L22, a pair of "tweezers" that hold together all the domains of the 23S rRNA. Interacts with the antibiotic troleandomycin which blocks the peptide exit tunnel.[HAMAP-Rule:MF_00340] [RL30_DEIRA] Binds the 5S and 23S rRNAs.[HAMAP-Rule:MF_01371] [RL33_DEIRA] Binds the 23S rRNA and the E site tRNA.[HAMAP-Rule:MF_00294] [RL2_DEIRA] One of the primary rRNA binding proteins. Required for association of the 30S and 50S subunits to form the 70S ribosome, for tRNA binding and peptide bond formation. It has been suggested to have peptidyltransferase activity; this is somewhat controversial. Makes several contacts with the 16S rRNA in the 70S ribosome (By similarity).[HAMAP-Rule:MF_01320_B] [RL11_DEIRA] This protein binds directly to 23S ribosomal RNA and also contacts the CTC protein (RL25).[HAMAP-Rule:MF_00736_B] [RL15_DEIRA] Binds to the 23S rRNA.[HAMAP-Rule:MF_01341_B] [RL17_DEIRA] Binds to the 23S rRNA.[HAMAP-Rule:MF_01368] [RL18_DEIRA] This is one of the proteins that binds and mediates the attachment of the 5S RNA into the large ribosomal subunit, where it forms part of the central protuberance.[HAMAP-Rule:MF_01337_B] [RL23_DEIRA] One of the early assembly protein (By similarity) it binds 23S rRNA. One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit. Forms the main docking site for trigger factor binding to the ribosome (PubMed:16091460 and PubMed:16271892).[HAMAP-Rule:MF_01369] [RL9_DEIRA] Binds to the 23S rRNA and protein L31.[HAMAP-Rule:MF_00503] [RL3_DEIRA] One of the primary rRNA binding proteins, it binds directly near the 3'-end of the 23S rRNA, where it nucleates assembly of the 50S subunit (By similarity).[HAMAP-Rule:MF_01325_B] [RL29_DEIRA] Binds the 23S rRNA. One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit.[HAMAP-Rule:MF_00374] [RL13_DEIRA] This protein is one of the early assembly proteins of the 50S ribosomal subunit (By similarity). Binds to the 23S rRNA.[HAMAP-Rule:MF_01366_B] [RL22_DEIRA] This protein binds specifically to 23S rRNA; its binding is stimulated by other ribosomal proteins, e.g. L4, L17, and L20. It is important during the early stages of 50S assembly. It makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit and ribosome (By similarity).[HAMAP-Rule:MF_01331_B] The globular domain of the protein is located by the polypeptide exit tunnel on the outside of the subunit while an extended beta-hairpin forms part of the wall of the tunnel. Forms a pair of "tweezers" with L32 that hold together two different domains of the 23S rRNA. Interacts with the tunnel-blocking modified macrolide azithromycin. Upon binding of the macrolide troleadomycin to the ribosome, the tip of the beta-hairpin is displaced, which severely restricts the tunnel. This and experiments in E.coli have led to the suggestion that it is part of the gating mechanism involved in translation arrest in the absence of the protein export system.[HAMAP-Rule:MF_01331_B] [RL36_DEIRA] Binds the 23S rRNA.[HAMAP-Rule:MF_00251] [RL4_DEIRA] One of the primary rRNA binding proteins, this protein initially binds near the 5'-end of the 23S rRNA. It is important during the early stages of 50S assembly (By similarity).[HAMAP-Rule:MF_01328_B] Makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit.[HAMAP-Rule:MF_01328_B] This protein is located close to the polypeptide exit tunnel, and interacts with the modified macrolide azithromycin, which blocks the tunnel.[HAMAP-Rule:MF_01328_B] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedTiamulin, a prominent member of the pleuromutilin class of antibiotics, is a potent inhibitor of protein synthesis in bacteria. Up to now the effect of pleuromutilins on the ribosome has not been determined on a molecular level. The 3.5 A structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin provides for the first time a detailed picture of its interactions with the 23S rRNA, thus explaining the molecular mechanism of the antimicrobial activity of the pleuromutilin class of antibiotics. Our results show that tiamulin is located within the peptidyl transferase center (PTC) of the 50S ribosomal subunit with its tricyclic mutilin core positioned in a tight pocket at the A-tRNA binding site. Also, the extension, which protrudes from its mutilin core, partially overlaps with the P-tRNA binding site. Thereby, tiamulin directly inhibits peptide bond formation. Comparison of the tiamulin binding site with other PTC targeting drugs, like chloramphenicol, clindamycin and streptogramins, may facilitate the design of modified or hybridized drugs that extend the applicability of this class of antibiotics. Inhibition of peptide bond formation by pleuromutilins: the structure of the 50S ribosomal subunit from Deinococcus radiodurans in complex with tiamulin.,Schlunzen F, Pyetan E, Fucini P, Yonath A, Harms JM Mol Microbiol. 2004 Dec;54(5):1287-94. PMID:15554968[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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