Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site.
Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site.
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Cryo-EM通过隐性结合位点揭示了USP1抑制的机制。
DOI：
10.1126/sciadv.abq6353
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发表时间：
2022-09-30
期刊：
影响因子：
13.6
通讯作者：
Walden, Helen
中科院分区：
文献类型：
--
作者：
Rennie, Martin L.;Arkinson, Connor;Chaugule, Viduth K.;Walden, Helen
DNA损伤对基因组完整性至关重要，并且在癌症特异性蛋白1（USP1）中经常破坏。电子显微镜研究USP1的组装酶抑制剂复合物和良好的抑制剂ML323具有2.5-Å的分辨率，有或没有ML323，我们发现了一个不寻常的结合模式，其中抑制剂会破坏下来的综合型构造。这些结构为基于结构的药物提供了平台针对USP1的设计。
ML323替换一部分蛋白质折叠，从而抑制了癌症靶标的USP1，从而在变构中破坏了活性位点。
Repair of DNA damage is critical to genomic integrity and frequently disrupted in cancers. Ubiquitin-specific protease 1 (USP1), a nucleus-localized deubiquitinase, lies at the interface of multiple DNA repair pathways and is a promising drug target for certain cancers. Although multiple inhibitors of this enzyme, including one in phase 1 clinical trials, have been established, their binding mode is unknown. Here, we use cryo–electron microscopy to study an assembled enzyme-substrate-inhibitor complex of USP1 and the well-established inhibitor, ML323. Achieving 2.5-Å resolution, with and without ML323, we find an unusual binding mode in which the inhibitor disrupts part of the hydrophobic core of USP1. The consequent conformational changes in the secondary structure lead to subtle rearrangements in the active site that underlie the mechanism of inhibition. These structures provide a platform for structure-based drug design targeting USP1. USP1, a cancer target, is inhibited by ML323 replacing part of the protein fold, allosterically disrupting the active site.
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DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
16.6
作者：
Coleman KE;Yin Y;Lui SKL;Keegan S;Fenyo D;Smith DJ;Rothenberg E;Huang TT
通讯作者：
Huang TT
影响因子：
14.8
作者：
Liang, Qin;Dexheimer, Thomas S.;Zhang, Ping;Rosenthal, Andrew S.;Villamil, Mark A.;You, Changjun;Zhang, Qiuting;Chen, Junjun;Ott, Christine A.;Sun, Hongmao;Luci, Diane K.;Yuan, Bifeng;Simeonov, Anton;Jadhav, Ajit;Xiao, Hui;Wang, Yinsheng;Maloney, David J.;Zhuang, Zhihao
通讯作者：
Zhuang, Zhihao
影响因子：
16
作者：
Cohn, Martin A.;Kowal, Przemyslaw;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.