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DOI | 10.1038/s41467-019-11295-6 |
Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme | |
Lv, Zongyang1,2; Yuan, Lingmin1,2; Atkison, James H.1,2; Williams, Katelyn M.1,2; Vega, Ramir3; Sessions, E. Hampton4; Divlianska, Daniela B.4; Davies, Christopher1,2; Chen, Yuan3; Olsen, Shaun K.1,2 | |
2019-08-06 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | 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. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000452042200002 |
WOS关键词 | PROTEIN-ACTIVATION ; CRYSTAL-STRUCTURE ; UBIQUITIN ; SUMOYLATION ; INSIGHTS ; CONJUGATION ; HUNTINGTIN ; REVEALS ; BINDING |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204486 |
专题 | 资源环境科学 |
作者单位 | 1.Med Univ South Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA; 2.Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA; 3.Beckman Res Inst City Hope, Dept Mol Med, Duarte, CA 91010 USA; 4.Sanford Burnham Prebys Med Discovery Inst Lake No, Conrad Prebys Ctr Chem Genom, Orlando, FL 32827 USA |
推荐引用方式 GB/T 7714 | Lv, Zongyang,Yuan, Lingmin,Atkison, James H.,et al. Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme[J]. NATURE COMMUNICATIONS,2019,9. |
APA | Lv, Zongyang.,Yuan, Lingmin.,Atkison, James H..,Williams, Katelyn M..,Vega, Ramir.,...&Olsen, Shaun K..(2019).Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme.NATURE COMMUNICATIONS,9. |
MLA | Lv, Zongyang,et al."Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme".NATURE COMMUNICATIONS 9(2019). |
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