Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.
Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.
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DOI：
10.1038/s41467-021-26546-8
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发表时间：
2021-10-27
影响因子：
16.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Chen J;Liu N;Huang Y;Wang Y;Sun Y;Wu Q;Li D;Gao S;Wang HW;Huang N;Qi X;Wang X
分子胶是一类介导蛋白质-蛋白质相互作用的小分子药物，可诱导目标蛋白质的降解或稳定。一组结构多样的化学物质，包括 17-β-雌二醇 (E2)、阿那格雷、nauclefine 和 DNMDP，通过与磷酸二酯酶 3A (PDE3A) 和 Schlafen 12 蛋白 (SLFN12) 形成复合物来诱导细胞凋亡。它们通过与 PDE3A 酶口袋结合来实现这一点，从而允许化合物结合的 PDE3A 招募并稳定 SLFN12，从而阻止蛋白质翻译，导致细胞凋亡。在这项工作中，我们报告了从用阿那格雷、nauclefine 或 DNMDP 预处理的培养 HeLa 细胞中分离出的 PDE3A-SLFN12 复合物的高分辨率冷冻电子显微镜结构。 PDE3A-SLFN12 复合物呈现蝴蝶状形状，与这些小分子形成异四聚体，这些小分子被包装在 PDE3A 催化结构域的浅口袋中。由此产生的小分子修饰界面通过疏水相互作用与 SLFN12 的短螺旋 (E552-I558) 结合，从而将两种蛋白质“粘合”在一起。基于复杂的结构，我们设计并合成了已知用于治疗血小板增多症的药物阿那格雷的类似物，以增强其与SLFN12的相互作用，并在诱导培养细胞以及肿瘤异种移植物中取得了优异的凋亡效果。阿那格雷、nauclefine 和 DNMDP 通过与磷酸二酯酶 3A (PDE3A) 和 Schlafen 12 蛋白 (SLFN12) 形成复合物诱导细胞凋亡。在这里，作者展示了 PDE3A-SLFN12 复合物与这些化合物作为分子胶的冷冻电镜结构。基于复杂的结构，他们开发了一种阿那格雷类似物，该类似物在诱导培养细胞凋亡方面表现出更高的效力，并且还促进肿瘤异种移植物中的肿瘤生长抑制，这对于癌症药物的开发很有意义。
Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-β-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus “gluing” the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts. Anagrelide, nauclefine and DNMDP induce apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). Here, the authors present the cryo-EM structures of PDE3A-SLFN12 complexes with these compounds as molecular glues. Based on the complex structure, they developed an anagrelide analog that shows a higher potency in inducing apoptosis in cultured cells and also promotes tumor growth inhibition in tumor xenografts, which is of interest for cancer drug development.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
影响因子：
3
作者：
Pettersen, EF;Goddard, TD;Ferrin, TE
通讯作者：
Ferrin, TE
影响因子：
2.9
作者：
Pisareva, Vera P.;Muslimov, Ilham A.;Tcherepanov, Andrew;Pisarev, Andrey V.
通讯作者：
Pisarev, Andrey V.
DOI：
10.1016/j.bbrc.2008.03.032
发表时间：
2008-05-23
影响因子：
3.1
作者：
Neumann, Brent;Zhao, Liang;Gonda, Thomas J.
通讯作者：
Gonda, Thomas J.