Elucidation of New Binding Interactions with the Human Tsg101 Protein Using Modified HIV-1 Gag-p6 Derived Peptide Ligands
Elucidation of New Binding Interactions with the Human Tsg101 Protein Using Modified HIV-1 Gag-p6 Derived Peptide Ligands
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DOI：
10.1021/ml1002579
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发表时间：
2011-05-01
影响因子：
4.2
通讯作者：
Burke, Terrence R.
中科院分区：
文献类型：
--
作者：
Kim, Sung-Eun;Liu, Fa;Burke, Terrence R.
靶向蛋白质-蛋白质相互作用作为一种有吸引力的治疗方法正在获得更大的认可。这方面的一个例子可以在由肿瘤易感性基因101（Tsg 101）编码的人类细胞蛋白中找到，其中与新生病毒Gag蛋白的p6 C-末端结构域的相互作用是HIV-1颗粒出芽和释放所必需的。Gag与Tsg 101的这种结合高度依赖于p6蛋白内的“Pro-Thr-Ala-Pro”（“PTAP”）肽序列。尽管p6衍生肽提供了开发Tsg 101结合抑制剂的潜在起点，但典型肽的亲和力在有用范围之外（Kd值大于50 μ M）。本文报道了Tsg 101与两种结构修饰的PTAP衍生肽复合的晶体结构。这些数据定义了新的配体相互作用的区域，以前没有确定与典型的肽序列。这一信息可能是非常有用的Tsg 101结合拮抗剂的设计。
Targeting protein protein interactions is gaining greater recognition as an attractive approach to therapeutic development. An example of this may be found with the human cellular protein encoded by the tumor susceptibility gene 101 (Tsg101), where interaction with the p6 C-terminal domain of the nascent viral Gag protein is required for HIV-1 particle budding and release. This association of Gag with Tsg101 is highly dependent on a "Pro-Thr-Ala-Pro" ("PTAP") peptide sequence within the p6 protein. Although p6-derived peptides offer potential starting points for developing Tsg101-binding inhibitors, the affinities of canonical peptides are outside the useful range (K-d values greater than 50 mu M). Reported herein are crystal structures of Tsg101 in complex with two structurally modified PTAP-derived peptides. These data define new regions of ligand interaction not previously identified with canonical peptide sequences. This information could be highly useful in the design of Tsg101-binding antagonists.