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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。


A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase


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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