How binding of small molecule and peptide ligands to HIV-1 TAR alters the RNA motional landscape
How binding of small molecule and peptide ligands to HIV-1 TAR alters the RNA motional landscape
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DOI：
10.1093/nar/gkn1074
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发表时间：
2009-04-01
影响因子：
14.9
通讯作者：
Varani, Gabriele
中科院分区：
文献类型：
--
作者：
Bardaro, Michael F., Jr.;Shajani, Zahra;Varani, Gabriele
HIV-1 TAR RNA代表了研究RNA功能中动力学和构象变化的作用的众所周知的范例。这种调节RNA响应于达特蛋白和各种肽和小分子配体的结合而改变构象，表明其构象灵活性和内在动力学在分子识别中起重要作用。我们已经使用C-13 NMR弛豫实验来检查HIV-1 TAR在三种不同亲和力和特异性的配体存在下的运动景观的变化。配体是烟酰胺，一种达特碱性结构域的线性肽模拟物和一种有效抑制Tat依赖性转录激活的环状肽。所有三种分子在代表Tat结合位点的三个核苷酸凸起内诱导相同的运动特征。然而，环肽在顶端环中具有独特的运动特征，其代表了必需的宿主辅因子细胞周期蛋白T1的结合位点。这些结果表明，所有的肽模拟物的达特诱导相同的动力学在TAR内的蛋白结合位点。然而，新的环状肽模拟物的达特代表了一类新的配体与独特的影响的动力学和顶端环的结构。
The HIV-1 TAR RNA represents a well-known paradigm to study the role of dynamics and conformational change in RNA function. This regulatory RNA changes conformation in response to binding of Tat protein and of a variety of peptidic and small molecule ligands, indicating that its conformational flexibility and intrinsic dynamics play important roles in molecular recognition. We have used C-13 NMR relaxation experiments to examine changes in the motional landscape of HIV-1 TAR in the presence of three ligands of different affinity and specificity. The ligands are argininamide, a linear peptide mimic of the Tat basic domain and a cyclic peptide that potently inhibits Tat-dependent activation of transcription. All three molecules induce the same motional characteristics within the three nucleotides bulge that represents the Tat-binding site. However, the cyclic peptide has a unique motional signature in the apical loop, which represents a binding site for the essential host co-factor cyclin T1. These results suggest that all peptidic mimics of Tat induce the same dynamics in TAR within this protein binding site. However, the new cyclic peptide mimic of Tat represents a new class of ligands with a unique effect on the dynamics and the structure of the apical loop.