...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Defective Hydrophobic Sliding Mechanism and Active Site Expansion in HIV-1 Protease Drug Resistant Variant Gly48Thr/Leu89Met: Mechanisms for the Loss of Saquinavir Binding Potency
【24h】

Defective Hydrophobic Sliding Mechanism and Active Site Expansion in HIV-1 Protease Drug Resistant Variant Gly48Thr/Leu89Met: Mechanisms for the Loss of Saquinavir Binding Potency

机译：HIV-1蛋白酶抗药性变异Gly48Thr / Leu89Met中的疏水疏水滑动机制和活性位点扩展：沙奎那韦结合力丧失的机制。

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

HIV drug resistance continues to emerge; consequently, there is an urgent need to develop next generation antiretroviral therapeutics.(1) Here we report on the structural and kinetic effects of an HIV protease drug resistant variant with the double mutations Gly48Thr and Leu89Met (PRG48T/L89M), without the stabilizing mutations Gln7Lys, Leu33Ile, and Leu63Ile. Kinetic analyses reveal that PRG48T/L89M and PRWT share nearly identical Michaelis-Menten parameters; however, PRG48T/L89M exhibits weaker binding for IDV (41-fold), SQV (18-fold), APV (15-fold), and NFV (9-fold) relative to PRWT. A 1.9 angstrom resolution crystal structure was solved for PRG48T/L89M bound with saquinavir (PRG48T/L89M-SQV) and compared to the crystal structure of PRWT bound with saquinavir (PRWT-SQV). PRG48T/L89M-SQV has an enlarged active site resulting in the loss of a hydrogen bond in the S3 subsite from Gly48 to P3 of SQV, as well as less favorable hydrophobic packing interactions between P1 Phe of SQV and the S1 subsite. PRG48T/L89M-SQV assumes a more open conformation relative to PRWT-SQV, as illustrated by the downward displacement of the fulcrum and elbows and weaker interatomic flap interactions. We also show that the Leu89Met mutation disrupts the hydrophobic sliding mechanism by causing a redistribution of van der Waals interactions in the hydrophobic core in PRG48T/L89M-SQV. Our mechanism for PRG48T/L89M-SQV drug resistance proposes that a defective hydrophobic sliding mechanism results in modified conformational dynamics of the protease. As a consequence, the protease is unable to achieve a fully closed conformation that results in an expanded active site and weaker inhibitor binding.
机译：艾滋病毒耐药性继续显现;因此，迫切需要开发下一代抗逆转录病毒疗法。（1）在此，我们报道了具有双重突变Gly48Thr和Leu89Met（PRG48T / L89M）且没有稳定突变的HIV蛋白酶耐药变异体的结构和动力学作用。 Gln7Lys，Leu33Ile和Leu63Ile。动力学分析表明，PRG48T / L89M和PRWT具有几乎相同的Michaelis-Menten参数。但是，相对于PRWT，PRG48T / L89M对IDV（41倍），SQV（18倍），APV（15倍）和NFV（9倍）的结合较弱。解析了与沙奎那韦结合的PRG48T / L89M（PRG48T / L89M-SQV）的1.9埃分辨率晶体结构，并与与沙奎那韦结合的PRWT的晶体结构（PRWT-SQV）进行了比较。 PRG48T / L89M-SQV的活性位点扩大，导致S3子位点从Gly48到SQV的P3失去了氢键，并且SQV的P1 Phe和S1子位点之间的疏水性填充相互作用减弱。 PRG48T / L89M-SQV相对于PRWT-SQV呈现更开放的构象，如支点和肘部的向下移位以及较弱的原子间瓣相互作用说明。我们还显示，Leu89Met突变通过在PRG48T / L89M-SQV疏水核中引起范德华相互作用的重新分布而破坏了疏水滑动机制。我们的PRG48T / L89M-SQV耐药性机制提示，疏水性滑动机制缺陷会导致蛋白酶的构象动力学发生变化。结果，蛋白酶不能实现完全封闭的构象，从而导致扩展的活性位点和较弱的抑制剂结合。

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