Structure of TAR RNA complexed with a Tat-TAR interaction nanomolar inhibitor that was identified by computational screening
Structure of TAR RNA complexed with a Tat-TAR interaction nanomolar inhibitor that was identified by computational screening
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DOI：
10.1016/s1074-5521(02)00151-5
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发表时间：
2002-06-01
影响因子：
--
通讯作者：
James, TL
中科院分区：
文献类型：
--
作者：
Du, ZH;Lind, KE;James, TL
HIV-1 TAR RNA通过结合反激活调节蛋白Tat在病毒复制中起关键作用。我们最近在实验中发现了几种在100 nM浓度下完全抑制Tat-TAR相互作用的化合物。我们使用了针对TAR 11三维结构的181,000种化合物的有效化学目录的计算筛选。在这里，我们报道了核磁共振衍生的TAR与乙酰丙嗪络合的结构。该结构代表了一类生物利用度好、毒性低、与TAR结合亲和力高的新型化合物。核磁共振数据明确表明，乙酰丙氨酸仅与Tat蛋白结合的独特的5'凸起位点结合。结合的特异性和亲和力主要是由碱基堆叠和疏水相互作用的网络赋予的。乙酰丙嗪对游离TAR结构的改变小于Tat肽和新霉素。
HIV-1 TAR RNA functions critically in viral replication by binding the transactivating regulatory protein Tat. We recently identified several compounds that experimentally inhibit the Tat-TAR interaction completely at a 100 nM concentration. We used computational screening of the 181,000-compound Available Chemicals Directory against the three-dimensional structure of TAR 11]. Here we report the NMR-derived structure of TAR complexed with acetylpromazine. This structure represents a new class of compounds with good bioavailability and low toxicity that bind with high affinity to TAR. NMR data unambiguously show that acetylpromazine binds only to the unique 5' bulge site to which the Tat protein binds. Specificity and affinity of binding are conferred primarily by a network of base stacking and hydrophobic interactions. Acetylpromazine alters the structure of free TAR less than Tat peptides and neomycin do.