Mutations outside the anisomycin-binding site can make ribosomes drug-resistant

被引:67
作者
Blaha, Gregor [1 ]
Gurel, Guliz [2 ]
Schroeder, Susan J. [2 ]
Moore, Peter B. [1 ,2 ]
Steitz, Thomas A. [1 ,2 ,3 ]
机构
[1] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[2] Yale Univ, Dept Chem, New Haven, CT 06520 USA
[3] Howard Hughes Med Inst, New Haven, CT 06520 USA
关键词
antibiotic resistance; large ribosomal subunit; 23S rRNA mutation; X-ray crystal structure; Haloarcula marismortui;
D O I
10.1016/j.jmb.2008.03.075
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Eleven mutations that make Haloarcula marismortui resistant to anisomycin, an antibiotic that competes with the amino acid side chains of aminoacyl tRNAs for binding to the A-site cleft of the large ribosomal unit, have been identified in 23S rRNA. The correlation observed between the sensitivity of H. marismortui to anisomycin and the affinity of its large ribosomal subunits for the drug indicates that its response to anisomycin is determined primarily by the binding of the drug to its large ribosomal subunit. The structures of large ribosomal subunits containing resistance mutations show that these mutations can be divided into two classes: (1) those that interfere with specific drug-ribosome interactions and (2) those that stabilize the apo conformation of the A-site cleft of the ribosome relative to its drug-bound conformation. The conformational effects of some mutations of the second kind propagate through the ribosome for considerable distances and are reversed when A-site substrates bind to the ribosome. (c) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:505 / 519
页数:15
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