Correlating conformational shift induction with altered inhibitor potency in a multidrug resistant HIV-1 protease variant.
Correlating conformational shift induction with altered inhibitor potency in a multidrug resistant HIV-1 protease variant.
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DOI：
10.1021/bi301010z
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发表时间：
2012-10-09
期刊：
影响因子：
2.9
通讯作者：
Fanucci GE
中科院分区：
文献类型：
--
作者：
de Vera IM;Blackburn ME;Fanucci GE
多重耐药 HIV-1 蛋白酶变体 MDR769 中抑制剂诱导的构象整体变化通过定点自旋标记 (SDSL) 双电子共振 (DEER) 光谱进行了表征。对于 MDR769 而言，与天然酶相比，抑制剂 IC50 值的变化与定义为 |ΔC| 的参数相关，该参数是抑制剂诱导的向关闭状态转变的相对变化。具体来说，|ΔC|之间存在线性相关性。以及 IC50 的倍数变化，前提是抑制剂结合不太弱。此外，表现出 MDR769 抗性的抑制剂不再诱导向封闭构象整体的强烈转变，如之前在天然酶中看到的那样。
Inhibitor-induced conformational ensemble shifts in a multi-drug resistant HIV-1 protease variant, MDR769, are characterized by site-directed spin labeling (SDSL) double electron-electron resonance (DEER) spectroscopy. For MDR769 compared to native enzyme, changes in inhibitor IC50 values are related to a parameter defined as |ΔC|, which is the relative change in the inhibitor-induced shift to the closed state. Specifically, a linear correlation is found between |ΔC| and the fold-change in IC50, provided that inhibitor-binding is not too weak. Moreover, inhibitors that exhibit MDR769 resistance no longer induce a strong shift to a closed conformational ensemble as seen previously in native enzyme.