7eg4

Cryo-EM structure of nauclefine-induced PDE3A-SLFN12 complex

spinqualitylabelsall models 7eg4, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7eg4 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.2Å Ligands: MG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PDE3A_HUMAN Brachydactyly-arterial hypertension syndrome. The disease is caused by variants affecting the gene represented in this entry. Function PDE3A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[UniProtKB:Q9Z0X4] Publication Abstract from PubMed 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-beta-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. Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.,Chen J, Liu N, Huang Y, Wang Y, Sun Y, Wu Q, Li D, Gao S, Wang HW, Huang N, Qi X, Wang X Nat Commun. 2021 Oct 27;12(1):6204. doi: 10.1038/s41467-021-26546-8. PMID:34707099 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphodiesterase 3D structures

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