title: Structural characterization of an alternative mode of tigecycline binding to the bacterial ribosome.
abstract: Although both tetracycline and tigecycline inhibit protein synthesis by sterically hindering the binding of tRNA to the ribosomal A site, tigecycline shows increased efficacy in both in vitro and in vivo activity assays and escapes the most common resistance mechanisms associated with the tetracycline class of antibiotics. These differences in activities are attributed to the tert-butyl-glycylamido side chain found in tigecycline. Our structural analysis by X-ray crystallography shows that tigecycline binds the bacterial 30S ribosomal subunit with its tail in an extended conformation and makes extensive interactions with the 16S rRNA nucleotide C1054. These interactions restrict the mobility of C1054 and contribute to the antimicrobial activity of tigecycline, including its resistance to the ribosomal protection proteins.
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedlbauer
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kaminishi
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Ochoa-Lizarralde
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Neha
authors.initials: N
authors.lastname: Dhimole
authors.affiliation: Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain.
authors.forename: Jorge P
authors.initials: JP
authors.lastname: López-Alonso
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain IKERBASQUE, Basque Foundation for Science, Bilbao, Spain sean.connell@gmail.com pfucini@cicbiogune.es.
authors.forename: Sean R
authors.identifier: http://orcid.org/0000-0001-7807-7049
authors.initials: SR
authors.lastname: Connell
authors.affiliation: Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt, Frankfurt am Main, Germany Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany IKERBASQUE, Basque Foundation for Science, Bilbao, Spain sean.connell@gmail.com pfucini@cicbiogune.es.
authors.forename: Paola
authors.initials: P
authors.lastname: Fucini
mesh_terms: D018360:Crystallography, X-Ray; D008911:Minocycline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D016963:Thermus thermophilus / Q000187:drug effects / Q000378:metabolism; D000078304:Tigecycline
chemical_list: D012336:RNA, Ribosomal, 16S; D000078304:Tigecycline; D008911:Minocycline