4aqy
From Proteopedia
Structure of ribosome-apramycin complexes
Structural highlights
Function[RSHX_THETH] Binds at the top of the head of the 30S subunit. It stabilizes a number of different RNA elements and thus is important for subunit structure (By similarity). [RS7_THET8] One of the primary rRNA binding proteins, it binds directly to 3'-end of the 16S rRNA where it nucleates assembly of the head domain of the 30S subunit. Is located at the subunit interface close to the decoding center. Binds mRNA and the E site tRNA blocking its exit path in the ribosome. This blockage implies that this section of the ribosome must be able to move to release the deacetylated tRNA.[HAMAP-Rule:MF_00480_B] [RS17_THETH] One of the primary rRNA binding proteins, it binds specifically to the 5'-end of 16S ribosomal RNA (By similarity). [RS16_THETH] Binds to the lower part of the body of the 30S subunit, where it stabilizes two of its domains. [RS6_THETH] Located on the outer edge of the platform on the body of the 30S subunit (By similarity). [RS12_THETH] With S4 and S5 plays an important role in translational accuracy (By similarity).[HAMAP-Rule:MF_00403_B] Interacts with and stabilizes bases of the 16S rRNA that are involved in tRNA selection in the A site and with the mRNA backbone. Located at the interface of the 30S and 50S subunits, it traverses the body of the 30S subunit contacting proteins on the other side and probably holding the rRNA structure together. The combined cluster of proteins S8, S12 and S17 appears to hold together the shoulder and platform of the 30S subunit (By similarity).[HAMAP-Rule:MF_00403_B] [RS14Z_THETH] Binds 16S rRNA, required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site (By similarity). [RS15_THETH] One of the primary rRNA binding proteins, it binds directly to 16S rRNA where it helps nucleate assembly of the platform of the 30S subunit by binding and bridging several RNA helices of the 16S rRNA. Forms an intersubunit bridge (bridge B4) with the 23S rRNA of the 50S subunit in the ribosome (By similarity). [RS8_THETH] One of the primary rRNA binding proteins, it binds directly to 16S rRNA central domain where it helps coordinate assembly of the platform of the 30S subunit (By similarity). [RS4_THET8] One of the primary rRNA binding proteins, it binds directly to 16S rRNA where it helps nucleate assembly of the body and platform of the 30S subunit. Binds mRNA in the 70S ribosome, positioning it for translation.[HAMAP-Rule:MF_01306_B] [RS10_THETH] Involved in the binding of tRNA to the ribosomes (By similarity). [RS19_THETH] Protein S19 forms a complex with S13 that binds strongly to the 16S ribosomal RNA (By similarity). [RS5_THETH] With S4 and S12 plays an important role in translational accuracy (By similarity).[HAMAP-Rule:MF_01307_B] Located at the back of the 30S subunit body where it stabilizes the conformation of the head with respect to the body (By similarity).[HAMAP-Rule:MF_01307_B] Publication Abstract from PubMedAminoglycosides are potent antibacterials, but therapy is compromised by substantial toxicity causing, in particular, irreversible hearing loss. Aminoglycoside ototoxicity occurs both in a sporadic dose-dependent and in a genetically predisposed fashion. We recently have developed a mechanistic concept that postulates a key role for the mitochondrial ribosome (mitoribosome) in aminoglycoside ototoxicity. We now report on the surprising finding that apramycin, a structurally unique aminoglycoside licensed for veterinary use, shows little activity toward eukaryotic ribosomes, including hybrid ribosomes which were genetically engineered to carry the mitoribosomal aminoglycoside-susceptibility A1555G allele. In ex vivo cultures of cochlear explants and in the in vivo guinea pig model of chronic ototoxicity, apramycin causes only little hair cell damage and hearing loss but it is a potent antibacterial with good activity against a range of clinical pathogens, including multidrug-resistant Mycobacterium tuberculosis. These data provide proof of concept that antibacterial activity can be dissected from aminoglycoside ototoxicity. Together with 3D structures of apramycin-ribosome complexes at 3.5-A resolution, our results provide a conceptual framework for further development of less toxic aminoglycosides by hypothesis-driven chemical synthesis. Dissociation of antibacterial activity and aminoglycoside ototoxicity in the 4-monosubstituted 2-deoxystreptamine apramycin.,Matt T, Ng CL, Lang K, Sha SH, Akbergenov R, Shcherbakov D, Meyer M, Duscha S, Xie J, Dubbaka SR, Perez-Fernandez D, Vasella A, Ramakrishnan V, Schacht J, Bottger EC Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):10984-9. Epub 2012 Jun 14. PMID:22699498[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Large Structures | Thermus thermophilus | Akbergenov, R | Bottger, E C | Dubbaka, S R | Duscha, S | Lang, K | Matt, T | Meyer, M | Ng, C L | Perez-Fernandez, D | Ramakrishnan, V | Schacht, J | Sha, S H | Shcherbakov, D | Vasella, A | Xie, J | Apramycin | Ribosome | Toxicity
