Peptomyc S.L., Edifici Cellex, 08035 Barcelona, Spain.
Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, 08035 Barcelona, Spain.
Cells. 2020 Apr 22;9(4):1038. doi: 10.3390/cells9041038.
Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is still surprisingly limited. Indubitably though, its crucial and non-redundant role in cancer biology makes it an attractive target. However, achieving successful clinical Myc inhibition has proven challenging so far, as this nuclear protein is an intrinsically disordered polypeptide devoid of any classical ligand binding pockets. Indeed, Myc only adopts a (partially) folded structure in some contexts and upon interacting with some protein partners, for instance when dimerizing with MAX to bind DNA. Here, we review the cumulative knowledge on Myc structure and biophysics and discuss the implications for its biological function and the development of improved Myc inhibitors. We focus this biophysical walkthrough mainly on the basic region helix-loop-helix leucine zipper motif (bHLHLZ), as it has been the principal target for inhibitory approaches so far.
Myc 是一种转录因子，能够驱动细胞的生长和增殖，并参与大多数人类肿瘤。尽管有大量关于这个关键致癌基因的文献，但我们对其功能的确切分子决定因素和机制的理解仍然惊人地有限。然而，毫无疑问，它在癌症生物学中的关键和不可或缺的作用使其成为一个有吸引力的靶点。然而，迄今为止，实现成功的临床 Myc 抑制一直具有挑战性，因为这种核蛋白是一种无任何经典配体结合口袋的固有无序多肽。事实上，Myc 只有在某些情况下才会采用（部分）折叠结构，并与某些蛋白质伙伴相互作用，例如与 MAX 二聚化以结合 DNA 时。在这里，我们回顾了关于 Myc 结构和生物物理学的累积知识，并讨论了其对生物学功能的影响以及开发改进的 Myc 抑制剂的意义。我们主要关注基本区域螺旋-环-螺旋亮氨酸拉链模体（bHLHLZ），因为迄今为止它一直是抑制方法的主要目标。
