Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes
Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes
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DOI：
10.1074/jbc.m809096200
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发表时间：
2009-03-27
影响因子：
4.8
通讯作者：
Lisztwan, Joanna
中科院分区：
文献类型：
--
作者：
Kallen, Joerg;Goepfert, Arnaud;Lisztwan, Joanna
P53的抑癌活性通过与致癌蛋白Hdm2和HdmX的结合而被负调控。P53残基Leu(26)、Trp(23)和Phe(19)是调节这些相互作用的关键。抑制p53与Hdm2和HdmX的结合应该是在癌症背景下重新激活P53的一种有前途的临床方法，但先前的研究表明，发现双重Hdm2/HdmX抑制剂将是困难的。我们测定了HdmX的N-末端结构域的1.3a处的晶体结构，它与两个不含和带有6-氯取代基的P53多肽结合(它与P53的Trp23结合在同一子口袋中)。后一种化合物是尚未被描述的最有效的基于多肽的P53-Hdm2相互作用拮抗剂。X射线结构揭示了HdmX结合裂隙的惊人构象变化，包括Tyr(99)的“开放构象”以及Trp和Leu口袋之间意想不到的“串扰”。值得注意的是，6-氯P53与HdmX和Hdm2都具有高亲和力(K-d值分别为36和7 nM)。我们的结果表明，开发有效的HdmX和Hdm2双重抑制剂是可行的。它们还揭示了HdmX可能的构象状态，这应该会导致对其与潜在生物伙伴相互作用的更好预测。
p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu(26), Trp(23), and Phe(19) are crucial to mediate these interactions. Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult. We have determined the crystal structures at 1.3A of the N-terminal domain of HdmX bound to two p53 peptidomimetics without and with a 6-chlorine substituent on the indole (which binds in the same subpocket as Trp23 of p53). The latter compound is the most potent peptide-based antagonist of the p53-Hdm2 interaction yet to be described. The x-ray structures revealed surprising conformational changes of the binding cleft of HdmX, including an "open conformation" of Tyr(99) and unexpected "cross-talk" between the Trp and Leu pockets. Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2(K-d values of 36 and 7 nM, respectively). Our results suggest that the development of potent dual inhibitors for HdmX and Hdm2 should be feasible. They also reveal possible conformational states of HdmX, which should lead to a better prediction of its interactions with potential biological partners.