• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Molecular Biology >Negative Epistasis and Evolvability in TEM-1 beta-Lactamase-The Thin Line between an Enzyme's Conformational Freedom and Disorder
【24h】

Negative Epistasis and Evolvability in TEM-1 beta-Lactamase-The Thin Line between an Enzyme's Conformational Freedom and Disorder

机译：TEM-1β-内酰胺酶的阴性超声和进化 - 酶构象自由和紊乱之间的细线

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Epistasis is a key factor in evolution since it determines which combinations of mutations provide adaptive solutions and which mutational pathways toward these solutions are accessible by natural selection. There is growing evidence for the pervasiveness of sign epistasis a complete reversion of mutational effects, particularly in protein evolution yet its molecular basis remains poorly understood. We describe the structural basis of sign epistasis between G238S and R164S, two adaptive mutations in TEM-1 beta-lactamase- an enzyme that endows antibiotics resistance. Separated by 10 A, these mutations initiate two separate trajectories toward increased hydrolysis rates and resistance toward second and third-generation cephalosporins antibiotics. Both mutations allow the enzyme's active site to adopt alternative conformations and accommodate the new antibiotics. By solving the corresponding set of crystal structures, we found that R164S causes local disorder whereas G2385 induces discrete conformations. When combined, the mutations in 238 and 164 induce local disorder whereby nonproductive conformations that perturb the enzyme's catalytic preorganization dominate. Specifically, Asn170 that coordinates the deacylating water molecule is misaligned, in both the free form and the inhibitor-bound double mutant. This local disorder is not restored by stabilizing global suppressor mutations and thus leads to an evolutionary cul-de-sac. Conformational dynamism therefore underlines the reshaping potential of protein's structures and functions but also limits protein evolvability because of the fragility of the interactions networks that maintain protein structures. (C) 2015 Elsevier Ltd. All rights reserved.
机译：Epistasis是演变的关键因素，因为它决定了哪种突变组合提供了自适应解决方案，并且可以通过自然选择来获得朝向这些溶液的突变途径。符号简化普遍存在的普遍性恢复的普遍性越来越多的证据，特别是在蛋白质演化中，其分子基础仍然很清楚。我们描述了G238S和R164s之间的符号简化的结构基础，TEM-1β-内酰胺酶的两个适应性突变，赋予抗生素抗性的酶。用10A分离，这些突变引发了两个单独的轨迹朝着增加的水解率和抗抗性的抗生素和第三代头孢菌素抗生素。均突变允许酶的活性位点采用替代构象并适应新的抗生素。通过求解相应的晶体结构，我们发现R164S导致局部疾病，而G2385引起离散构象。结合时，238和164中的突变诱导局部疾病，从而扰乱酶的催化整合占诱导的非培养构象。具体地，在自由形式和抑制剂结合的双突变体中，坐标坐标的ASN170未alaliged。通过稳定全球抑制突变，不会恢复该局部疾病，从而导致进化的Cul-De-sac。因此，构象活力强调了蛋白质结构和功能的重塑潜力，而且因此由于维持蛋白质结构的相互作用网络的脆弱性而限​​制了蛋白质不溶解性。 （c）2015 Elsevier Ltd.保留所有权利。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号