Nucleotide Dynamics at the A-Site Cleft in the Peptidyltransferase Center of H. marismortui 50S Ribosomal Subunits
详细信息 查看全文
- 作者：Yuhang Wang ; Jana K. Shen ; Susan J. Schroeder
- 刊名：The Journal of Physical Chemistry Letters
- 出版年：2012
- 出版时间：April 19, 2012
- 年：2012
- 卷：3
- 期：8
- 页码：1007-1010
- 全文大小：315K
- 年卷期：v.3,no.8(April 19, 2012)
- ISSN：1948-7185
文摘
Resistance mutations to antibiotics targeting rRNA can be far from the drug-binding site. Crystallography studies revealed that the antibiotic resistance mutation G2482A (G2447A in E. coli) in Haloarcula marismortui 50S ribosomes does not directly contact the drug or introduce changes to the ribosomal structure except for losing a potassium ion coordinated to a base triple at the drug-binding site. Using molecular dynamics simulations, we tested hypotheses regarding the effects of the G2482A mutation and ion coordination on the conformational dynamics of the 50S ribosome. Simulations show that the mutation enhances conformational fluctuation at the antibiotic binding site, weakens the hydrogen-bonding network, and increases flexibility at the 50S peptidyl transferase center (PTC). Our data supports the view that distant mutations can perturb the dynamic network in the ribosomal PTC, thereby raising the entropic cost of antibiotic binding. These results underscore the importance of considering conformational dynamics in rational drug design.