Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme
Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme
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DOI：
10.1038/s41467-018-07015-1
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发表时间：
2018-12-04
影响因子：
16.6
通讯作者：
Olsen, Shaun K.
中科院分区：
文献类型：
--
作者：
Lv, Zongyang;Yuan, Lingmin;Olsen, Shaun K.
在泛素/泛素结合级联的第一步，E1酶激活泛素(Ub)和泛素样修饰物(UBL)，是癌症和其他危及生命的疾病治疗干预的潜在靶点。在这里，我们报告了Ubl相扑的E1酶与最近发现的高度特异的共价变构抑制剂(COH000)的复合体的晶体结构。该结构揭示了COH000以一个不同于活性部位的隐蔽口袋为靶点，而活性部位完全被埋在所有以前的相扑E1结构中，并且COH000与相扑E1的结合伴随着一个结构变化网络，该网络完全将酶锁定在以前未观察到的非活性构象中。这些结构变化包括活性部位的分解和含有半胱氨酸的催化SCCH结构域相对于准备催化腺基化的SUMO E1的构象快照180度旋转。综上所述，我们的研究为COH000的抑制机制及其SUMO E1的特异性提供了分子基础，并为在隐蔽的变构位点上针对其他UBL的E1酶的潜在分子开发奠定了基础。
E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. These structural changes include disassembly of the active site and a 180 degrees rotation of the catalytic cysteine-containing SCCH domain, relative to conformational snapshots of SUMO E1 poised to catalyze adenylation. Altogether, our study provides a molecular basis for the inhibitory mechanism of COH000 and its SUMO E1 specificity, and also establishes a framework for potential development of molecules targeting E1 enzymes for other Ubls at a cryptic allosteric site.