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Nature:变成药物治疗对象的抗肿瘤目标

摘要 : 免疫调控药物如thalidomide、lenalidomide 和 pomalidomide已证明对骨髓瘤有疗效。

 免疫调控药物如thalidomide、lenalidomide 和 pomalidomide已证明对骨髓瘤有疗效。这些药物通过 “E3泛素连接酶” CRL4CRBN 的基质受体部分 “cereblon” (CRBN)定向作用于CRL4CRBN (CUL4–DDB1–RBX1–cereblon)。在这项研究中,Mary E. Matyskiela 等人识别出一种新的免疫调控药物,即CC-885,它以一个不同的基质为作用目标,该基质就是 “翻译终止因子” GSPT1。来自患者的急性骨髓性白血病肿瘤细胞对CC-885高度敏感。作者还获得了CRBN–DDB1–CC-885–GSPT1复合物的晶体结构,发现GSPT1在其表面上以相同方式与这种酶和这种药物结合。另一个cereblon 基质,即Ikaros,也通过一个类似的结构特征与该 “药物-酶”复合物结合,这可能意味着该药物对基质增补(substrate recruitment)采用一个共同的主题。

原文链接:

A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase

原文摘要:

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4CRBN E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN–DDB1–CC-885–GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a ‘hotspot’ on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon ‘neosubstrate’ selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

来源: Nature 浏览次数:1

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