4AQY

Structure of ribosome-apramycin complexes

Summary for 4AQY

• Entry DOI: 10.2210/pdb4aqy/pdb
• Related: 1AB3 1AN7 1CQM 1CQN 1DV4 1EG0 1EMW 1FJG 1FKA 1GIX 1HNW 1HNX 1HNZ 1HR0 1I94 1I95 1I96 1I97 1IBK 1IBL 1IBM 1J5E 1JGO 1JGP 1JGQ 1KUQ 1L1U 1LOU 1MVR 1N32 1N33 1N34 1N36 1PNS 1PNX 1QD7 1QJH 1QKF 1QKH 1RIS 1RSS 1TWT 1VOX 1VOZ 1XMO 1XMQ 1XNQ 1XNR 1YL4 2B64 2B9M 2B9O 2BVZ 2BXJ 2F4V 2J00 2J02 2JL7 2UU9 2UUA 2UUB 2UUC 2UXB 2UXC 2UXD 2V46 2V48 2VQE 2VQF 2WDG 2WDH 2WDK 2WDM 2WH1 2WH3 2WRN 2WRQ 2X9R 2X9T 2XFZ 2XG1 2XQD 2XSY 2XUY 2Y0U 2Y0W 2Y0Y 2Y10 2Y12 2Y14 2Y18 3ZVO 4ABR
• Descriptor: 16S RIBOSOMAL RNA, 30S RIBOSOMAL PROTEIN S10, 30S RIBOSOMAL PROTEIN S11, ... (28 entities in total)
• Functional Keywords: ribosome, apramycin, toxicity
• Biological source: THERMUS THERMOPHILUS; More
• Total number of polymer chains: 23
• Total formula weight: 797512.44

Authors

Matt, T.,Ng, C.L.,Lang, K.,Sha, S.H.,Akbergenov, R.,Shcherbakov, D.,Meyer, M.,Duscha, S.,Xie, J.,Dubbaka, S.R.,Perez-Fernandez, D.,Vasella, A.,Ramakrishnan, V.,Schacht, J.,Bottger, E.C. (deposition date: 2012-04-20, release date: 2012-07-18, Last modification date: 2023-12-20)

Primary citation

Matt, T.,Ng, C.L.,Lang, K.,Sha, S.H.,Akbergenov, R.,Shcherbakov, D.,Meyer, M.,Duscha, S.,Xie, J.,Dubbaka, S.R.,Perez-Fernandez, D.,Vasella, A.,Ramakrishnan, V.,Schacht, J.,Bottger, E.C.
Dissociation of Antibacterial Activity and Aminoglycoside Ototoxicity in the 4-Monosubstituted 2-Deoxystreptamine Apramycin.
Proc.Natl.Acad.Sci.USA, 109:10984-, 2012

PubMed Abstract: Aminoglycosides 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-Å resolution, our results provide a conceptual framework for further development of less toxic aminoglycosides by hypothesis-driven chemical synthesis.

PubMed: 22699498
DOI: 10.1073/PNAS.1204073109

Experimental method

X-RAY DIFFRACTION (3.5 Å)