Conformational landscape of non-B variants of HIV-1 protease: A pulsed EPR study
Conformational landscape of non-B variants of HIV-1 protease: A pulsed EPR study
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DOI：
10.1016/j.bbrc.2020.08.030
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发表时间：
2020-11-05
影响因子：
3.1
通讯作者：
Fanucci，Gail E.
中科院分区：
文献类型：
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作者：
Tran，Trang T.;Liu，Zhanglong;Fanucci，Gail E.
HIV感染是一种全球性的健康流行病，目前FDA批准的HIV-1蛋白酶抑制剂（PI）针对亚型B蛋白酶设计，但它们在全球范围内用于HIV治疗，而不考虑患者的HIV分类。在这项研究中，双电子-电子共振（DEER）电子顺磁共振（EPR）光谱被用来获得洞察力在几个非洲和巴西的蛋白酶（PR）变体的天然多态性如何影响构象景观在不存在和存在抑制剂。研究结果表明，亚型F和H HIV-1 PR在未结合状态下主要采用闭合构象，并有两个二级突变D 60 E和I62 V，据推测这两个突变导致闭合构象的概率增加。相比之下，亚型D、CRF_AG和CRF_BF HIV-1 PR主要采用半开放构象，与PI初治亚型B在未结合底物或抑制剂时观察到的情况相同。还表征了抑制剂结合对这些变体的构象景观转变的影响，其中分析提供了抑制剂诱导的从半开放状态转变为弱、中等和强效应的分类。将这些结果与PI初治亚型B、C和CRF_AE中抑制剂诱导构象变化的既往研究结果进行比较。
HIV infection is a global health epidemic with current FDA-approved HIV-1 Protease inhibitors (PIs) designed against subtype B protease, yet they are used in HIV treatment world-wide regardless of patient HIV classification. In this study, double electron-electron resonance (DEER) electron paramagnetic resonance (EPR) spectroscopy was utilized to gain insights in how natural polymorphisms in several African and Brazilian protease (PR) variants affect the conformational landscape both in the absence and presence of inhibitors. Findings show that Subtypes F and H HIV-1 PR adopt a primarily closed conformation in the unbound state with two secondary mutations, D60E and I62V, postulated to be responsible for the increased probability for closed conformation. In contrast, subtype D, CRF_AG, and CRF_BF HIV-1 PR adopt a primarily semi-open conformation, as observed for PI-naïve-subtype B when unbound by substrate or inhibitor. The impact that inhibitor binding has on shifting the conformational land scape of these variants is also characterized, where analysis provides classification of inhibitor induced shifts away from the semi-open state into weak, moderate and strong effects. The findings are compared to those for prior studies of inhibitor induced conformational shifts in PI-naïve Subtype B, C and CRF_AE.