Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions.
Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions.
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DOI：
10.1016/j.str.2020.12.001
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发表时间：
2021-03-04
期刊：
影响因子：
--
通讯作者：
Van Duyne GD
中科院分区：
文献类型：
--
作者：
Gupta K;Allen A;Giraldo C;Eilers G;Sharp R;Hwang Y;Murali H;Cruz K;Janmey P;Bushman F;Van Duyne GD
变构HIV整合酶(IN)抑制剂(ALLINI)的主要作用是在病毒粒子成熟期间观察到，Allini治疗通过药物诱导的IN聚集来中断IN-RNA相互作用，导致异常病毒粒子的形成。为了了解伴随药物诱导的聚集的结构变化，我们测定了Allini诱导的IN聚集的软物质属性。利用小角中子散射(SANS)、扫描电子显微镜(SEM)和流变学研究发现，AlLINI诱导的高阶聚集体具有弱三维凝胶的特征，具有类分形体的特征。它们的形成被宿主因子LEDGF/p75以及体外抗性替换所抑制。诱变和生物物理分析表明，同质羧基末端结构域(CTD)的相互作用是实现Allini诱导的聚集体的支化聚合物性质所必需的。这些研究为在Allini发挥作用的拥挤的病毒粒子环境中Allini的作用和抗性机制提供了关键的见解。变构HIV整合酶(IN)抑制剂(ALLINI)是一种有效的抗病毒药物，可诱导IN的不适当聚集。我们报道了这些聚集体的软物质性质，发现了一种具有分形性的支化聚合物，并且需要同质的羧基-末端结构域相互作用才能形成这些三维网络。
The major effect of allosteric HIV integrase (IN) inhibitors (ALLINIs) is observed during virion maturation, where ALLINI treatment interrupts IN-RNA interactions via drug-induced IN aggregation, leading to the formation of aberrant virions. To understand the structural changes that accompany drug-induced aggregation, we determined the soft matter properties of ALLINI-induced IN aggregates. Using small-angle neutron scattering (SANS), scanning electron microscopy (SEM), and rheology, we have discovered that the higher-order aggregates induced by ALLINIs have the characteristics of weak three-dimensional gels with a fractal-like character. Their formation is inhibited by the host factor LEDGF/p75, as well as ex vivo resistance substitutions. Mutagenesis and biophysical analyses reveal that homomeric carboxy-terminal domain (CTD) interactions are required to achieve the branched polymer nature of the ALLINI-induced aggregates. These studies provide key insight into the mechanisms of ALLINI action and resistance in the context of the crowded virion environment where ALLINIs exert their effect. Allosteric HIV integrase (IN) inhibitors (ALLINIs) are potent antivirals that induce the inappropriate aggregation of IN. We report on the soft matter properties of these aggregates, discovering a branched polymer with fractal-like character and that homomeric carboxy-terminal domain interactions are required to form these 3-D networks.
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影响因子：
5.9
作者：
Cihlar, Tomas;Fordyce, Marshall
通讯作者：
Fordyce, Marshall
影响因子：
8.6
作者：
BALE, HD;SCHMIDT, PW
通讯作者：
SCHMIDT, PW
影响因子：
2.9
作者：
Deprez, E;Tauc, P;Brochon, JC
通讯作者：
Brochon, JC
DOI：
10.1073/pnas.150220297
发表时间：
2000-07-18
影响因子：
11.1
作者：
Chen, JCH;Krucinski, J;Stroud, RM
通讯作者：
Stroud, RM
DOI：
10.1126/science.aah7002
发表时间：
2017-01-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ballandras-Colas A;Maskell DP;Serrao E;Locke J;Swuec P;Jónsson SR;Kotecha A;Cook NJ;Pye VE;Taylor IA;Andrésdóttir V;Engelman AN;Costa A;Cherepanov P
通讯作者：
Cherepanov P