Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1.
Critical Non-Covalent Binding Intermediate for an Allosteric Covalent Inhibitor of SUMO E1.
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DOI：
10.1021/acs.jpclett.3c00253
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发表时间：
2023-03-23
影响因子：
5.7
通讯作者：
Miao, Yinglong
中科院分区：
文献类型：
--
作者：
Pawnikar, Shristi;Bhattarai, Apurba;Ouyang, S. Xiaohu;Vega, Ramir;Chen, Yuan;Miao, Yinglong
小泛素样修饰物（SUMO）的翻译后修饰在许多类型的癌症中失调。SUMO E1酶最近被建议作为一种新的免疫肿瘤学靶点。COH 000是一种高度特异性的SUMO E1变构共价抑制剂。然而，显着的差异被发现之间的X-射线结构的共价COH 000结合SUMO E1复合物和可用的结构-活性-关系（SAR）的抑制剂类似物的数据，由于未解决的非共价蛋白质-配体相互作用。在这里，我们研究了COH 000和SUMO E1之间的非共价相互作用，通过新的配体高斯加速分子动力学（LiGaMD）模拟抑制剂解离。我们的模拟已经确定了关键的低能量非共价结合的中间构象的COH 000，同意与发表的和新的SAR数据的COH 000类似物，否则与X射线结构不一致。总之，我们的生化实验和LiGaMD模拟已经发现了一个关键的非共价结合中间体在变构抑制的SUMO E1复合物。
Post-translational modifications by small ubiquitin-like modifiers (SUMO) are dysregulated in many types of cancers. SUMO E1 enzyme has recently been suggested as a new immuno-oncology target. COH000 was recently identified as a highly specific allosteric covalent inhibitor of the SUMO E1. However, marked discrepancy was found between X-ray structure of the covalent COH000-bound SUMO E1 complex and available structure-activity-relationship (SAR) data of inhibitor analogs due to unresolved non-covalent protein-ligand interactions. Here, we have investigated non-covalent interactions between COH000 and SUMO E1 during the inhibitor dissociation through novel Ligand Gaussian accelerated Molecular Dynamics (LiGaMD) simulations. Our simulations have identified critical low-energy non-covalent binding intermediate conformation of COH000 that agreed excellently with published and new SAR data of the COH000 analogs, which were otherwise inconsistent with X-ray structure. Altogether, our biochemical experiments and LiGaMD simulations have uncovered a critical non-covalent binding intermediate during allosteric inhibition of the SUMO E1 complex.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1073/pnas.1802114115
发表时间：
2018-06-26
影响因子：
11.1
作者：
Crowl JT;Stetson DB
通讯作者：
Stetson DB
影响因子：
4.4
作者：
Wang, Jinan;Miao, Yinglong
通讯作者：
Miao, Yinglong
影响因子：
64.8
作者：
HAYWARD, WS;NEEL, BG;ASTRIN, SM
通讯作者：
ASTRIN, SM
影响因子：
30.5
作者：
Decque, Adrien;Joffre, Olivier;Dejean, Anne
通讯作者：
Dejean, Anne